Formulations of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4methylcyclohexylamino)-pyrimidine-5-carboxamide

ABSTRACT

Provided are pharmaceutical compositions and dosage forms of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, or a pharmaceutically acceptable stereoisomer, tautomer, solid form, polymorph, salt, hydrate, clathrate, or solvate thereof. Also provided are methods of treating, managing, or preventing various disorders, such as diseases or disorders treatable or preventable by inhibition of a JNK pathway in mammals using such pharmaceutical compositions or dosage forms. Further provided are salts of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide and methods of preparation of such salts.

This application is a continuation of U.S. application Ser. No.14/969,750, filed Dec. 15, 2015, currently allowed, which claims thebenefit of U.S. Provisional Application No. 62/196,044, filed Jul. 23,2015, and U.S. Provisional Application No. 62/092,537, filed Dec. 16,2014, the contents of each of which are incorporated by reference hereinin their entirety.

1. FIELD

Provided herein are pharmaceutical compositions, dosage forms and saltsof2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide.Methods for using the pharmaceutical compositions, dosage forms andsalts are also provided herein.

2. BACKGROUND

The connection between abnormal protein phosphorylation and the cause orconsequence of diseases has been known for over 20 years. Accordingly,protein kinases have become a very important group of drug targets. (SeeCohen, Nature, 1:309-315 (2002), Gaestel et al. Curr. Med. Chem. 14:2214-223 (2007); Grimminger et al. Nat. Rev. Drug Disc. 9(12):956-970(2010)). Various protein kinase inhibitors have been used clinically inthe treatment of a wide variety of diseases, such as cancer and chronicinflammatory diseases, including rheumatoid arthritis and psoriasis.(See Cohen, Eur. J. Biochem., 268:5001-5010 (2001); Protein KinaseInhibitors for the Treatment of Disease: The Promise and the Problems,Handbook of Experimental Pharmacology, Springer Berlin Heidelberg, 167(2005)).

JNK is a ubiquitously expressed serine/threonine kinase belonging,together with ERK (extracellular-regulated kinase) and p38, to thefamily of mitogen-activated protein kinases (MAPKs). (Kyriakis J M, Sci.STKE (48):pel (2000); Whitmarsh A J, et al. Sci. STKE (1):pel (1999);Schramek H, News Physiol. Sci. 17:62-7 (2002); Ichijo H, Oncogene18(45):6087-93 (1999)). MAPKs are important mediators of signaltransduction from the cell surface to the nucleus, using phosphorylationcascades to generate a coordinated response by a cell to an externalstimulus by phosphorylation of selected intracellular proteins,including transcription factors. Additionally, JNK also phosphorylatesnon-nuclear proteins, for example, IRS-1, and Bcl-2 family members.(Davis R J, Trends Biochem. Sci. 9(11):470-473 (1994); Seger R et al.,FASEB J.; 9(9):726-35 (1995); Fanger G R et al., Curr. Opin. Genet.Dev.; 7(1):67-74 (1997)).

The elucidation of the intricacy of protein kinase pathways and thecomplexity of the relationship and interaction among and between thevarious protein kinases and kinase pathways highlights the importance ofdeveloping pharmaceutical agents capable of acting as protein kinasemodulators, regulators or inhibitors that have beneficial activity onmultiple kinases or multiple kinase pathways.

The compound chemically named2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide(alternatively named2-[(1,1-dimethylethyl)amino]-4-[[(1R,3R,4R)-3-hydroxy-4-methylcyclohexyl]amino]-5-pyrimidinecarboxamide)and tautomers thereof are disclosed in U.S. Patent ApplicationPublication No. 2013/0029987, published on Jan. 31, 2013, andInternational Pub. No. WO2012/145569, the entireties of each of whichare incorporated by reference herein.

The identification and selection of a formulation of a pharmaceuticalcompound is complex, given that a change in formulation may affect avariety of physical and chemical properties, which may provide benefitsor drawbacks in safety, processing, stability, solubility andbioavailability, among other important pharmaceutical characteristics.

Notably, the various excipients employed in a formulation of apharmaceutical compound can have a profound effect on the manufacturingprocess, wherein characteristics such as flowability (e.g., blend flow),hardness, compressibility, sticking, filming and capping can be affectedby the identity and amount of the excipients employed.

Citation or identification of any reference in Section 2 of thisapplication is not to be construed as an admission that the reference isprior art to the present application.

3. SUMMARY

Provided herein are pharmaceutical compositions and dosage formscomprising:

having the name2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide(alternatively named2-[(1,1-dimethylethyl)amino]-4-[[(1R,3R,4R)-3-hydroxy-4-methylcyclohexyl]amino]-5-pyrimidinecarboxamide)(Compound 1), or a pharmaceutically acceptable salt, stereoisomer,tautomer, solid form, polymorph, hydrate, clathrate, or solvate thereof(collectively referred to herein as “Compound A”).

Further provided herein are pharmaceutically acceptable salts ofCompound 1, including hydrochloride, sulfate, phosphate, L-tartrate,L-malate, L-lactate, succinate, p-toluenesulfate (tosylate),methanesulfate (mesylate), benzensulfate (besylate), fumarate andcitrate salts.

Further provided herein are methods for using the pharmaceuticalcompositions, and dosage forms of Compound A for treating or preventingdiseases or disorders treatable or preventable by inhibition of a JNKpathway, as described herein. Also provided herein is a pharmaceuticalcomposition of Compound A for use in a method of treating diseases ordisorders treatable or preventable by inhibition of a JNK pathway, asdescribed herein. Also provided herein is a dosage form of Compound Afor use in a method of treating diseases or disorders treatable orpreventable by inhibition of a JNK pathway, as described herein. Alsoprovided herein is a pharmaceutical composition of Compound A for use ina method of preventing diseases or disorders treatable or preventable byinhibition of a JNK pathway, as described herein. Also provided hereinis a dosage form of Compound A for use in a method of preventingdiseases or disorders treatable or preventable by inhibition of a JNKpathway, as described herein. In some embodiments, the diseases ordisorders include, but are not limited to, interstitial pulmonaryfibrosis, systemic sclerosis, scleroderma, chronic allograftnephropathy, antibody mediated rejection, or lupus. In otherembodiments, the diseases or disorders include, but are not limited to,liver fibrotic disorders, or diabetes and/or metabolic syndrome leadingto liver fibrotic disorders, as described herein.

Also provided are methods of preparing, isolating, and characterizingthe salts.

The present embodiments can be understood more fully by reference to thedetailed description and examples, which are intended to exemplifynon-limiting embodiments.

4. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the process and equipment for wet granulation processesof Compound 1 compositions.

FIG. 2 depicts dissolution profiles of Compound 1 tablets in 0.1 N HCl.

FIG. 3 depicts dissolution profiles of Compound 1 tablets in 0.01 N HCl.

FIG. 4 depicts dissolution profiles of Compound 1 tablets in an aqueoussolution at pH 4.5.

FIG. 5 depicts pharmacokinetic (PK) data of Compound 1 capsules andtablets in a dog.

FIG. 6 depicts an overlay of X-ray powder diffractogram (XRPD) patternsof Compound 1 (free base) isolated from ACN (previously named Form C),EtOH/IPA (previously named Form C), EtOAc (previously named Form G) oracetone (previously named Form B), Form A (initial material) and HClsalt forms 1-4 of Compound 1 isolated from ACN, EtOH/IPA, EtOAc oracetone (from top to bottom). The free base Forms A (labeled initialmaterial in FIGS. 6-13, 16-29), Form B, Form C and Form G werepreviously described in U.S. Provisional Patent Application No.61/933,636, filed on Jan. 30, 2014, and U.S. Provisional PatentApplication No. 62/025,161, filed on Jul. 16, 2014.

FIG. 7 depicts an overlay of Raman spectra of Compound 1 (free base)isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (initial material)and HCl salt forms 1-4 of Compound 1 isolated from ACN, EtOH/IPA, EtOAcor acetone (from top to bottom).

FIG. 8 depicts an overlay of XRPD patterns of Compound 1 (free base)isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (initial material)and H₂SO₄ salt forms 1-2 of Compound 1 isolated from ACN, IPA, EtOAc oracetone (from top to bottom).

FIG. 9 depicts an overlay of Raman spectra of Compound 1 (free base)isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (initial material)and H₂SO₄ salt forms 1-2 of Compound 1 isolated from ACN, IPA, EtOAc oracetone (from top to bottom).

FIG. 10 depicts an overlay of XRPD patterns of Compound 1 (free base)isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (initial material)and the H₃PO₄ salt of Compound 1 isolated from ACN, EtOH, EtOAc oracetone (from top to bottom).

FIG. 11 depicts an overlay of Raman spectra of Compound 1 (free base)isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (initial material)and the H₃PO₄ salt of Compound 1 isolated from ACN, EtOH, EtOAc oracetone (from top to bottom).

FIG. 12 depicts an overlay of XRPD patterns of Compound 1 (free base)isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (initial material)and the L-tartrate salt of Compound 1 isolated from ACN, EtOH, EtOAc oracetone (from top to bottom).

FIG. 13 depicts an overlay of Raman spectra of Compound 1 (free base)isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (initial material)and the L-tartrate salt of Compound 1 isolated from ACN, EtOH, EtOAc oracetone (from top to bottom).

FIG. 14 depicts a ¹H NMR spectrum of the L-tartrate salt of Compound 1prepared from acetone.

FIG. 15 depicts a TGA/DSC thermogram of the L-tartrate salt of Compound1 prepared from acetone.

FIG. 16 depicts an overlay of XRPD patterns of Compound 1 (free base)isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (initial material)and L-lactate salt forms 1-2 of Compound 1 isolated from ACN, hexane,EtOAc or acetone (from top to bottom).

FIG. 17 depicts an overlay of Raman spectra of Compound 1 (free base)isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (initial material)and L-lactate salt forms 1-2 of Compound 1 isolated from ACN, hexane,EtOAc or acetone (from top to bottom).

FIG. 18 depicts an overlay of XRPD patterns of Compound 1 (free base)isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (initial material)and L-malate salt forms 1-4 of Compound 1 isolated from ACN, MeNO₂,EtOAc or IPA (from top to bottom).

FIG. 19 depicts an overlay of Raman spectra of Compound 1 (free base)isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (initial material)and L-malate salt forms 1-4 of Compound 1 isolated from ACN, MeNO₂,EtOAc or IPA (from top to bottom).

FIG. 20 depicts an overlay of XRPD patterns of Compound 1 (free base)isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (initial material)and the L-malate salt of Compound 1 isolated from MTBE, MeNO₂, hexane orMeOAc (from top to bottom).

FIG. 21 depicts an overlay of Raman spectra of Compound 1 (free base)isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (initial material)and the L-malate salt of Compound 1 isolated from MTBE, MeNO₂, hexane orMeOAc (from top to bottom).

FIG. 22 depicts an overlay of XRPD patterns of Compound 1 (free base)isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (initial material)and succinate salt forms 1-2 and their mixture of Compound 1 isolatedfrom ACN, EtOH, EtOAc or acetone (from top to bottom).

FIG. 23 depicts an overlay of Raman spectra of Compound 1 (free base)isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (initial material)and succinate salt forms 1-2 and their mixture of Compound 1 isolatedfrom ACN, EtOH, EtOAc or acetone (from top to bottom).

FIG. 24 depicts an overlay of XRPD patterns of Compound 1 (free base)isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (initial material)and tosylate salt forms 1-3 of Compound 1 isolated from ACN, MeNO₂,EtOAc or acetone (from top to bottom).

FIG. 25 depicts an overlay of Raman spectra of Compound 1 (free base)isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (initial material)and tosylate salt forms 1-3 of Compound 1 isolated from ACN, MeNO₂,EtOAc or acetone (from top to bottom).

FIG. 26 depicts an overlay of XRPD patterns of Compound 1 (free base)isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (initial material)and mesylate salt forms 1-2 of Compound 1 isolated from ACN/IPA,EtOH/IPA, EtOAc or acetone (from top to bottom).

FIG. 27 depicts an overlay of Raman spectra of Compound 1 (free base)isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (initial material)and mesylate salt forms 1-2 of Compound 1 isolated from ACN/IPA,EtOH/IPA, EtOAc or acetone (from top to bottom).

FIG. 28 depicts an overlay of XRPD patterns of Compound 1 (free base)isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (initial material)and the fumarate salt isolated from ACN and the besylate salt isolatedfrom MeNO₂ (from top to bottom).

FIG. 29 depicts an overlay of Raman spectra of Compound 1 (free base)isolated from ACN, EtOH/IPA, EtOAc or acetone, Form A (initialmaterial), the fumarate salt isolated from ACN and the besylate saltisolated from MeNO₂ (from top to bottom).

FIG. 30 depicts an overlay of ¹H NMR spectra of the L-lactate salt,L-malate salt, L-tartrate salt, H₃PO₄ salt, H₂SO₄ salt, HCl salt andCompound 1 (free base) (from top to bottom).

FIG. 31 depicts photomicrographs of the HCl salt, H₂SO₄ salt, H₃PO₄salt, L-tartrate salt, L-malate salt, L-lactate salt and Compound 1(free base) (from left to right, and top to bottom).

FIG. 32 depicts an overlay of Raman spectra of Compound 1 (free base),the HCl salt, H₂SO₄ salt, H₃PO₄ salt, L-tartrate salt, L-malate salt andL-lactate salt (from top to bottom).

FIG. 33 depicts an overlay of XRPD patterns of Compound 1 (free base),the HCl salt, H₂SO₄ salt, H₃PO₄ salt, L-tartrate salt, L-malate salt andL-lactate salt (from top to bottom).

FIG. 34 depicts a TGA/DSC thermogram of form 2 of the HCl salt ofCompound 1.

FIG. 35 depicts a TGA/DSC thermogram of the H₂SO₄ salt of Compound 1.

FIG. 36 depicts a TGA/DSC thermogram of the H₃PO₄ salt of Compound 1.

FIG. 37 depicts a TGA/DSC thermogram of the L-tartrate salt of Compound1.

FIG. 38 depicts a TGA/DSC thermogram of the L-malate salt of Compound 1.

FIG. 39 depicts a TGA/DSC thermogram of the L-lactate salt of Compound1.

FIG. 40 depicts an overlay of ¹H NMR spectra of the L-lactate saltbefore and after heating (from top to bottom).

FIG. 41 depicts a DVS thermogram of the HCl salt of Compound 1.

FIG. 42 depicts an overlay of XRPD patterns of the HCl salt, thepost-DVS HCl salt, the HCl salt in water and the HCl salt in SimulatedGastric Fluid (SGF) (from top to bottom).

FIG. 43 depicts a DVS thermogram of the H₂SO₄ salt of Compound 1.

FIG. 44 depicts an overlay of XRPD patterns of the H₂SO₄ salt, thepost-DVS H₂SO₄ salt, the H₂SO₄ salt in water and the H₂SO₄ salt in SGF(from top to bottom).

FIG. 45 depicts a DVS thermogram of the H₃PO₄ salt of Compound 1.

FIG. 46 depicts an overlay of XRPD patterns of the H₃PO₄ salt, thepost-DVS H₃PO₄ salt, the H₃PO₄ salt in water and the H₃PO₄ salt in SGF(from top to bottom).

FIG. 47 depicts a DVS thermogram of the L-tartrate salt of Compound 1.

FIG. 48 depicts a DVS thermogram of the L-tartrate salt of Compound 1after preheated at 50° C. for 3 hours. (from top to bottom).

FIG. 49 depicts an overlay of XRPD patterns of the L-tartrate salt, thepost-DVS L-tartrate salt, the post-DVS L-tartrate salt after preheatedat 50° C. for 3 hours, the L-tartrate salt in water and the L-tartratesalt in SGF (from top to bottom).

FIG. 50 depicts a DVS thermogram of the L-malate salt of Compound 1.

FIG. 51 depicts an overlay of XRPD patterns of the L-malate salt, thepost-DVS L-malate salt, the L-malate salt in water and the L-malate saltin SGF (from top to bottom).

FIG. 52 depicts a DVS thermogram of the L-lactate salt of Compound 1.

FIG. 53 depicts an overlay of XRPD patterns of the L-lactate salt, thepost-DVS L-lactate salt, the L-lactate salt in water and the L-lactatesalt in SGF (from top to bottom).

FIG. 54 depicts an overlay of XRPD patterns of the L-H₂SO₄ salt in SGF,the L-malate salt in SGF, the L-tartrate salt in SGF, the H₃PO₄ salt,the L-lactate salt in SGF, Compound 1 (free base) in SGF, the HCl saltin SGF, the HCl salt and the HCl salt in water (from top to bottom).

FIG. 55 depicts an overlay of XRPD patterns of the HCl salt, the HClsalt stored at 80° C. for 2 weeks and the HCl salt stored at 80° C.under 75% relative humidity for two weeks (from top to bottom).

FIG. 56 depicts an overlay of Raman spectra of form 4, form 3, form 5,form 6, form 1 and form 2 of the HCl salt (from top to bottom).

FIG. 57 depicts an overlay of XRPD patterns of form 7, form 6, form 5,form 4, form 3, form 2 and form 1 of the HCl salt (from top to bottom).

FIG. 58 depicts a TGA/DSC thermogram of the HCl salt stored under 40°C./75% relative humidity for two weeks.

FIG. 59 depicts a TGA/DSC thermogram of form 6 of the HCl salt.

FIG. 60 depicts a DSC thermogram of form 1 of the HCl salt.

FIG. 61 depicts an overlay of XRPD patterns of the H₂SO₄ salt, the H₂SO₄salt stored at 80° C. for 2 weeks and the H₂SO₄ salt stored at 80° C.under 75% relative humidity for two weeks (from top to bottom).

FIG. 62 depicts an overlay of XRPD patterns of the H₃PO₄ salt, the H₃PO₄salt stored at 80° C. for 2 weeks and the H₃PO₄ salt stored at 80° C.under 75% relative humidity for two weeks (from top to bottom).

FIG. 63 depicts an overlay of XRPD patterns of the L-tartrate salt, theL-tartrate salt stored at 80° C. for 2 weeks and the L-tartrate saltstored at 80° C. under 75% relative humidity for two weeks (from top tobottom).

FIG. 64 depicts an overlay of XRPD-DSC patterns of the L-tartrate salt.

FIG. 65 depicts an overlay of XRPD patterns of the L-tartrate saltbefore and after heated to 130° C.

FIG. 66 depicts an overlay of XRPD patterns of the L-malate salt, theL-malate salt stored at 80° C. for 2 weeks and the L-malate salt storedat 80° C. under 75% relative humidity for two weeks (from top tobottom).

FIG. 67 depicts an overlay of XRPD patterns of the L-lactate salt, theL-lactate salt stored at 80° C. for 2 weeks and the L-lactate saltstored at 80° C. under 75% relative humidity for two weeks (from top tobottom).

FIG. 68 depicts an overlay of HPLC chromatograms of the Compound 1 (freebase) stored at 80° C. for 2 weeks, Compound 1 (free base) and theCompound 1 (free base) stored at 80° C. under 75% relative humidity fortwo weeks (from top to bottom).

FIG. 69 depicts an overlay of HPLC chromatograms of the HCl salt storedat 80° C. under 75% relative humidity for two weeks, the HCl salt storedat 80° C. for 2 weeks and the HCl salt (from top to bottom).

FIG. 70 depicts an overlay of HPLC chromatograms of the H₂SO₄ saltstored at 80° C. under 75% relative humidity for two weeks, the H₂SO₄salt stored at 80° C. for 2 weeks and the H₂SO₄ salt (from top tobottom).

FIG. 71 depicts an overlay of HPLC chromatograms of the H₃PO₄ saltstored at 80° C. under 75% relative humidity for two weeks, the H₃PO₄salt stored at 80° C. for 2 weeks and the H₃PO₄ salt (from top tobottom).

FIG. 72 depicts an overlay of HPLC chromatograms of the L-tartrate saltstored at 80° C. under 75% relative humidity for two weeks, theL-tartrate salt stored at 80° C. for 2 weeks and the L-tartrate salt(from top to bottom).

FIG. 73 depicts an overlay of HPLC chromatograms of the L-malate saltstored at 80° C. under 75% relative humidity for two weeks, the L-malatesalt stored at 80° C. for 2 weeks and the L-malate salt (from top tobottom).

FIG. 74 depicts an overlay of HPLC chromatograms of the L-lactate saltstored at 80° C. under 75% relative humidity for two weeks, theL-lactate salt stored at 80° C. for 2 weeks and the L-lactate salt (fromtop to bottom).

FIG. 75 depicts an XRPD pattern of HCl salt form 1.

FIG. 76 depicts an XRPD pattern of HCl salt form 2.

FIG. 77 depicts an XRPD pattern of HCl salt form 3.

FIG. 78 depicts an XRPD pattern of HCl salt form 4.

FIG. 79 depicts an XRPD pattern of HCl salt form 5.

FIG. 80 depicts an XRPD pattern of HCl salt form 6.

FIG. 81 depicts an XRPD pattern of HCl salt form 7.

FIG. 82 depicts an XRPD pattern of H₂SO₄ salt form 1.

FIG. 83 depicts an XRPD pattern of H₂SO₄ salt form 2.

FIG. 84 depicts an XRPD pattern of H₂SO₄ salt form 3, obtained fromH₂SO₄ salt form 1 when stored under 80° C./75% RH conditions for 2weeks.

FIG. 85 depicts an XRPD pattern of the H₃PO₄ salt.

FIG. 86 depicts an XRPD pattern of L-lactate salt form 1.

FIG. 87 depicts an XRPD pattern of L-lactate salt form 2.

FIG. 88 depicts an XRPD pattern of L-tartrate salt form 1.

FIG. 89 depicts an XRPD pattern of L-tartrate salt form 2.

FIG. 90 depicts an XRPD pattern of L-malate salt form 1.

FIG. 91 depicts an XRPD pattern of L-malate salt form 2.

FIG. 92 depicts an XRPD pattern of L-malate salt form 3.

FIG. 93 depicts an XRPD pattern of L-malate salt form 4.

FIG. 94 depicts an XRPD pattern of succinate salt form 1.

FIG. 95 depicts an XRPD pattern of succinate salt form 2.

FIG. 96 depicts an XRPD pattern of tosylate salt form 1.

FIG. 97 depicts an XRPD pattern of tosylate salt form 2.

FIG. 98 depicts an XRPD pattern of tosylate salt form 3.

FIG. 99 depicts an XRPD pattern of mesylate salt form 1.

FIG. 100 depicts an XRPD pattern of mesylate salt form 2.

FIG. 101 depicts an XRPD pattern of the besylate salt.

FIG. 102 depicts an XRPD pattern of the fumarate salt.

FIG. 103 depicts arithmetic mean (±SD) plasma concentrations of Compound1 in healthy subjects following multiple doses (qd×6 days) of Compound 1(Part 1).

FIG. 104 depicts arithmetic mean (±SD) plasma concentrations of Compound1 in healthy subjects following a single dose of Compound 1 under fastedand fed conditions in a study of Compound 1 (Part 2).

FIG. 105 depicts arithmetic mean (±SD) plasma concentrations of Compound1 in healthy subjects following a single dose of compound 1 under fastedconditions (Part 2).

FIG. 106 depicts plasma concentrations versus whole blood concentrationsof Compound 1 in healthy subjects following a single 200 mg dose ofCompound 1 (Part 2, Treatment D).

FIG. 107 depicts individual percentages of baseline phospho c-Junintegrated optical density scores.

FIG. 108 depicts changes from baseline in individual phospho c-Junimmunohistochemistry histology scores.

5. DETAILED DESCRIPTION 5.1. Definitions

As used herein, the term “pharmaceutically acceptable salt(s)” refers toa salt prepared from a pharmaceutically acceptable non-toxic acid orbase including an inorganic acid and base and an organic acid and base.Suitable pharmaceutically acceptable base addition salts include, butare not limited to metallic salts made from aluminum, calcium, lithium,magnesium, potassium, sodium and zinc or organic salts made from lysine,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitablenon-toxic acids include, but are not limited to, inorganic and organicacids such as acetic, alginic, anthranilic, L-asparate, benzenesulfonic,benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric,furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic,phosphoric, propionic, salicylic, stearic, succinic, sulfanilic,sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxicacids include hydrochloric, hydrobromic, phosphoric, sulfuric, andmethanesulfonic acids. Examples of specific salts thus includehydrochloride and mesylate salts. Others are well-known in the art, seefor example, Remington's Pharmaceutical Sciences, 18^(th) eds., MackPublishing, Easton Pa. (1990) or Remington: The Science and Practice ofPharmacy, 19^(th) eds., Mack Publishing, Easton Pa. (1995).

As used herein and unless otherwise indicated, the term “stereoisomer”or “stereomerically pure” means one stereoisomer of a compound that issubstantially free of other stereoisomers of that compound. For example,a stereomerically pure compound having one chiral center will besubstantially free of the opposite enantiomer of the compound. Astereomerically pure compound having two chiral centers will besubstantially free of other diastereomers of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, greater than about 90% by weight ofone stereoisomer of the compound and less than about 10% by weight ofthe other stereoisomers of the compound, greater than about 95% byweight of one stereoisomer of the compound and less than about 5% byweight of the other stereoisomers of the compound, or greater than about97% by weight of one stereoisomer of the compound and less than about 3%by weight of the other stereoisomers of the compound. Compounds can havechiral centers and can occur as racemates, individual enantiomers ordiastereomers, and mixtures thereof. All such isomeric forms areincluded within the embodiments disclosed herein, including mixturesthereof. The use of stereomerically pure forms of such compounds, aswell as the use of mixtures of those forms are encompassed by theembodiments disclosed herein. For example, mixtures comprising equal orunequal amounts of the enantiomers of a particular compound may be usedin methods and compositions disclosed herein. These isomers may beasymmetrically synthesized or resolved using standard techniques such aschiral columns or chiral resolving agents. See, e.g., Jacques, J., etal., Enantiomers, Racemates and Resolutions (Wiley-Interscience, NewYork, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, N Y, 1962); andWilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268(E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972).

It should also be noted the compounds can include E and Z isomers, or amixture thereof, and cis and trans isomers or a mixture thereof. Incertain embodiments, compounds are isolated as either the cis or transisomer. In other embodiments, compounds are a mixture of the cis andtrans isomers.

As used herein, and in the specification and the accompanying claims,the indefinite articles “a” and “an” and the definite article “the”include plural as well as single referents, unless the context clearlyindicates otherwise.

As used herein, and unless otherwise specified, the terms “about” and“approximately,” when used in connection with doses, amounts, or weightpercent of ingredients of a composition or a dosage form, mean a dose,amount, or weight percent that is recognized by one of ordinary skill inthe art to provide a pharmacological effect equivalent to that obtainedfrom the specified dose, amount, or weight percent. In certainembodiments, the terms “about” and “approximately,” when used in thiscontext, contemplate a dose, amount, or weight percent within 30%,within 20%, within 15%, within 10%, or within 5%, of the specified dose,amount, or weight percent.

As used herein, and unless otherwise specified, a crystalline that is“pure,” i.e., substantially free of other crystalline or amorphoussolids, contains less than about 10% by weight of one or more othercrystalline or amorphous solids, less than about 5% by weight of one ormore other crystalline or amorphous solids, less than about 3% by weightof one or more other crystalline or amorphous solids, or less than about1% by weight of one or more other crystalline or amorphous solids.

As used herein, and unless otherwise specified, a solid form that is“substantially physically pure” is substantially free from other solidforms. In certain embodiments, a crystal form that is substantiallyphysically pure contains less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%,3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% of one or moreother solid forms on a weight basis. The detection of other solid formscan be accomplished by any method apparent to a person of ordinary skillin the art, including, but not limited to, diffraction analysis, thermalanalysis, elemental combustion analysis and/or spectroscopic analysis.

As used herein, and unless otherwise specified, a solid form that is“substantially chemically pure” is substantially free from otherchemical compounds (i.e., chemical impurities). In certain embodiments,a solid form that is substantially chemically pure contains less thanabout 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%,0.1%, 0.05%, or 0.01% of one or more other chemical compounds on aweight basis. The detection of other chemical compounds can beaccomplished by any method apparent to a person of ordinary skill in theart, including, but not limited to, methods of chemical analysis, suchas, e.g., mass spectrometry analysis, spectroscopic analysis, thermalanalysis, elemental combustion analysis and/or chromatographic analysis.

As used herein, and unless otherwise indicated, a chemical compound,solid form, or composition that is “substantially free” of anotherchemical compound, solid form, or composition means that the compound,solid form, or composition contains, in certain embodiments, less thanabout 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%0.1%, 0.05%, or 0.01% by weight of the other compound, solid form, orcomposition.

Unless otherwise specified, the terms “solvate” and “solvated,” as usedherein, refer to a solid form of a substance which contains solvent. Theterms “hydrate” and “hydrated” refer to a solvate wherein the solvent iswater. “Polymorphs of solvates” refer to the existence of more than onesolid form for a particular solvate composition. Similarly, “polymorphsof hydrates” refer to the existence of more than one solid form for aparticular hydrate composition. The term “desolvated solvate,” as usedherein, refers to a solid form of a substance which can be made byremoving the solvent from a solvate. The terms “solvate” and “solvated,”as used herein, can also refer to a solvate of a salt, cocrystal, ormolecular complex. The terms “hydrate” and “hydrated,” as used herein,can also refer to a hydrate of a salt, cocrystal, or molecular complex.

“Tautomers” refers to isomeric forms of a compound that are inequilibrium with each other. The concentrations of the isomeric formswill depend on the environment the compound is found in and may bedifferent depending upon, for example, whether the compound is a solidor is in an organic or aqueous solution. For example, in aqueoussolution, pyrazoles may exhibit the following isomeric forms, which arereferred to as tautomers of each other:

As readily understood by one skilled in the art, a wide variety offunctional groups and other structures may exhibit tautomerism and alltautomers of Compound 1 are within the scope of the present invention.

It should also be noted that Compound 1 can contain unnaturalproportions of atomic isotopes at one or more of the atoms. For example,Compound 1 may be radiolabeled with radioactive isotopes, such as forexample tritium (³H), or carbon-14 (¹⁴C), or may be isotopicallyenriched, such as with deuterium (²H), carbon-13 (¹³C), or nitrogen-15(¹⁵N). As used herein, an “isotopologue” is an isotopically enrichedcompound. The term “isotopically enriched” refers to an atom having anisotopic composition other than the natural isotopic composition of thatatom. “Isotopically enriched” may also refer to a compound containing atleast one atom having an isotopic composition other than the naturalisotopic composition of that atom. The term “isotopic composition”refers to the amount of each isotope present for a given atom.Radiolabeled and isotopically enriched compounds are useful astherapeutic agents, e.g., cancer and inflammation therapeutic agents,research reagents, e.g., binding assay reagents, and diagnostic agents,e.g., in vivo imaging agents. All isotopic variations of Compound 1 andor Compound A, whether radioactive or not, are intended to beencompassed within the scope of the embodiments provided herein. In someembodiments, there are provided isotopologues of Compound 1, forexample, the isotopologues are deuterium, carbon-13, or nitrogen-15enriched Compound 1 and/or Compound A.

Unless otherwise specified, the term “composition” as used herein isintended to encompass a product comprising the specified ingredient(s)(and in the specified amount(s), if indicated), as well as any productwhich results, directly or indirectly, from combination of the specifiedingredient(s) in the specified amount(s). By “pharmaceuticallyacceptable,” it is meant a diluent, excipient, or carrier in aformulation must be compatible with the other ingredient(s) of theformulation and not deleterious to the recipient thereof.

“JNK” means a protein or an isoform thereof expressed by a JNK1, JNK2,or JNK3 gene (Gupta, S., Barrett, T., Whitmarsh, A. J., Cavanagh, J.,Sluss, H. K., Derijard, B. and Davis, R. J. The EMBO J. 15:2760-2770(1996)).

“Treating” as used herein, means an alleviation, in whole or in part, ofa disorder, disease or condition, or one or more of the symptomsassociated with a disorder, disease, or condition, or slowing or haltingof further progression or worsening of those symptoms, or alleviating oreradicating the cause(s) of the disorder, disease, or condition itself.In one embodiment, the disorder is a condition treatable or preventableby inhibition of a JNK pathway, as described herein. In anotherembodiment, the disorder is selected from interstitial pulmonaryfibrosis, systemic sclerosis, scleroderma, chronic allograftnephropathy, antibody mediated rejection, or lupus. In yet anotherembodiment, the disorder is a liver fibrotic disorder, or diabetesand/or metabolic syndrome leading to liver fibrotic disorders, asdescribed herein. In some embodiments, the disorder is a liver fibroticdisorder, such as non-alcoholic steatohepatitis, steatosis (i.e. fattyliver), cirrhosis, primary sclerosing cholangitis, primary biliarycirrhosis, hepatitis, hepatocellular carcinoma, or liver fibrosiscoincident with chronic or repeated alcohol ingestion (alcoholichepatitis), with infection (e.g., viral infection such as HCV), withliver transplant, or with drug induced liver injury (e.g., acetaminophentoxicity). In some embodiments, “treating” means an alleviation, inwhole or in part, of a disorder, disease or condition, or symptomsassociated with diabetes or metabolic syndrome leading to liver fibroticdisorders, such as non-alcoholic steatohepatitis, steatosis (i.e. fattyliver), hepatitis or cirrhosis, or a slowing, or halting of furtherprogression or worsening of those symptoms. In one embodiment, thesymptom is jaundice.

“Preventing” as used herein, means a method of delaying and/orprecluding the onset, recurrence or spread, in whole or in part, of adisorder, disease or condition; barring a subject from acquiring adisorder, disease, or condition; or reducing a subject's risk ofacquiring a disorder, disease, or condition. In one embodiment, thedisorder is a condition treatable or preventable by inhibition of a JNKpathway, as described herein. In another embodiment, the disorder isselected from interstitial pulmonary fibrosis, systemic sclerosis,scleroderma, chronic allograft nephropathy, antibody mediated rejection,or lupus. In one embodiment, the disorder is a liver fibrotic disorder,or diabetes or metabolic syndrome leading to liver fibrotic disorders,as described herein, or symptoms thereof In another embodiment, thedisorder is selected from interstitial pulmonary fibrosis, systemicsclerosis, scleroderma, chronic allograft nephropathy, antibody mediatedrejection, or lupus. In yet another embodiment, the disorder is a liverfibrotic disorder, or diabetes and/or metabolic syndrome leading toliver fibrotic disorders, as described herein. In some embodiments, thedisorder is a liver fibrotic disorder, such as non-alcoholicsteatohepatitis, steatosis (i.e. fatty liver), cirrhosis, primarysclerosing cholangitis, primary biliary cirrhosis, hepatitis,hepatocellular carcinoma, or liver fibrosis coincident with chronic orrepeated alcohol ingestion (alcoholic hepatitis), with infection (e.g.,viral infection such as HCV), with liver transplant, or with druginduced liver injury (e.g., acetaminophen toxicity).

The term “effective amount” in connection with Compound 1 or Compound Ameans an amount capable of treating or preventing a disorder, disease orcondition, or symptoms thereof, disclosed herein.

“Patient” or “subject” is defined herein to include animals, such asmammals, including, but not limited to, primates (e.g., humans), cows,sheep, goats, horses, dogs, cats, rabbits, rats, mice, monkeys,chickens, turkeys, quails, or guinea pigs and the like, in oneembodiment a mammal, in another embodiment a human. In one embodiment, asubject is a human having or at risk for having interstitial pulmonaryfibrosis, systemic sclerosis, scleroderma, chronic allograftnephropathy, antibody mediated rejection, or lupus. In another, asubject is a human having or at risk for having liver fibrotic disordersor diabetes or metabolic syndrome leading to liver fibrotic disorders,or a condition, treatable or preventable by inhibition of a JNK pathway,or a symptom thereof. In one embodiment, a subject is fasted. In anotherembodiment, a subject is fed.

5.2. Compound 1

The compositions and methods of use provided herein relate to Compound1:

having the alternative names2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamideor2-[(1,1-dimethylethyl)amino]-4-[[(1R,3R,4R)-3-hydroxy-4-methylcyclohexyl]amino]-5-pyrimidinecarboxamide,or a pharmaceutically acceptable stereoisomer, tautomer, solid form,polymorph, salt, hydrate, clathrate, or solvate thereof (collectivelyreferred to as Compound A).

Compound A and Compound 1 can be prepared using reagents and methodsprovided herein or known in the art, including the methods provided inU.S. Patent Application Publication No. 2013/0029987, published on Jan.31, 2013, U.S. Provisional Patent Application No. 61/933,636, filed onJan. 30, 2014, U.S. Provisional Patent Application No. 62/025,161, filedon Jul. 16, 2014, and International Pub. No. WO2012/145569, the entirecontents of each of which are incorporated herein by reference.

Free base forms (Forms A, B, C, D, E, F, G, H, and I) were previouslydescribed in U.S. Provisional Patent Application No. 61/933,636, filedon Jan. 30, 2014, U.S. and Provisional Patent Application No.62/025,161, filed on Jul. 16, 2014.

It should be noted that if there is a discrepancy between a depictedstructure and a name given that structure, the depicted structure is tobe accorded more weight. In addition, if the stereochemistry of astructure or a portion of a structure is not indicated with, forexample, bold or dashed lines, the structure or portion of the structureis to be interpreted as encompassing all stereoisomers of it.

5.3. Pharmaceutical Compositions

Provided herein are pharmaceutical compositions and dosage forms ofCompound A. In some embodiments, the dosage forms are suitable for oraladministration to a patient. In other embodiments, the dosage formsprovided herein exhibit advantageous physical and/or pharmacologicalproperties. Such properties include, but are not limited to, ease ofassay, content uniformity, flow properties for manufacture, dissolutionand bioavailability, and stability.

Provided herein are kits comprising pharmaceutical compositions anddosage forms provided herein. Also provided herein are methods oftreating, managing, and/or preventing a disease or condition, whichcomprises administering to a patient in need thereof a pharmaceuticalcomposition or a dosage form provided herein.

In certain embodiments, the unit dosage forms provided herein are oraldosage forms.

In certain embodiments, the pharmaceutical compositions and dosage formsprovided herein are tablets.

5.4. Formulation A

In one embodiment, provided herein is a pharmaceutical compositioncomprising Compound A, and one or more pharmaceutically acceptableexcipients or carriers. In one embodiment, the pharmaceuticalcomposition is Formulation A comprising excipients or carriers describedin Table 1.

In one embodiment, provided herein is a pharmaceutical compositioncomprising Compound A and one or more pharmaceutically acceptableexcipients and carriers selected from diluents, surfactants,disintegrants and lubricants. In certain embodiments, the pharmaceuticalcompositions can be coated.

In certain embodiments, the diluents include, but are not limited to,mannitol (e.g., Mannitol 200), cellulose (e.g., microcrystallinecellulose, such as AVICEL® PH 101 and AVICEL® PH 102). In oneembodiment, the diluent is mannitol. In yet another embodiment, thediluent is Mannitol 200. In yet another embodiment, the diluent iscellulose. In yet another embodiment, the diluent is microcrystallinecellulose. In yet another embodiment, the diluent is AVICEL® PH 101. Instill another embodiment, the diluent is AVICEL® PH 102.

In certain embodiments, the surfactants include, but are not limited to,hydroxypropyl methycellulose (HPMC) (e.g., Methocel™ K3). In oneembodiment, the surfactant is Methocel™ K3.

In certain embodiments, the disintegrants include, but are not limitedto, carboxymethyl cellulose (e.g., croscarmellose sodium, such asAC-DI-SOL®). In one embodiment, the disintegrant is carboxymethylcellulose. In another embodiment, the disintegrant is croscarmellosesodium. In still another embodiment, the disintegrant is AC-DI-SOL®.

In one embodiment, the lubricant is magnesium stearate.

In certain embodiments, the coating includes, but is not limited to,Opadry (e.g., Opadry yellow, Opadry white and Opadry brown). In oneembodiment, the coating is Opadry. In another embodiment, the coating isOpadry yellow. In another embodiment, the coating is Opadry white. Inanother embodiment, the coating is Opadry brown.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A and one or more pharmaceutically acceptableexcipients or carriers, each independently selected from mannitol,cellulose, HPMC, carboxymethyl cellulose and magnesium stearate. Incertain embodiments, the pharmaceutical compositions are coated withOpadry.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A and one or more pharmaceutically acceptableexcipients or carriers, each independently selected from mannitol,microcrystalline cellulose, HPMC, croscarmellose sodium and magnesiumstearate. In certain embodiments, the pharmaceutical compositions arecoated with Opadry.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A and one or more pharmaceutically acceptableexcipients or carriers, each independently selected from Mannitol 200,AVICEL® PH 101, AVICEL® PH 102, Methocel™ K3, AC-DI-SOL® and magnesiumstearate. In certain embodiments, the pharmaceutical compositions arecoated with Opadry white, Opadry yellow or Opadry brown.

In one embodiment, provided herein is a pharmaceutical compositioncomprising Compound A, a diluent(s)/binder(s), a disintegrant(s), asurfactant(s) and a lubricant(s). In certain embodiments, thepharmaceutical compositions are coated.

In one embodiment, provided herein is a pharmaceutical compositioncomprising Compound A, mannitol and magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising Compound A, mannitol, cellulose and magnesium stearate.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A, mannitol, microcrystalline cellulose,carboxymethyl cellulose and magnesium stearate.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A, mannitol, microcrystalline cellulose,croscarmellose sodium and magnesium stearate.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A, Mannitol 200, AVICEL® PH 101, AC-DI-SOL®,Methocel™ K3 and magnesium stearate.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A, Mannitol 200, AVICEL® PH 102, AC-DI-SOL®,Methocel™ K3 and magnesium stearate.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A, Mannitol 200, AVICEL® PH 101, AVICEL® PH 102,AC-DI-SOL®, Methocel™ K3 and magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 20-40% by weight of Compound A, about 50-70% by weightof diluent(s)/binder(s), about 1-10% by weight of disintegrant(s), about1-10% by weight of surfactant(s) and about 0.1-2% by weight oflubricant(s).

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 28.57% by weight of Compound A, about 63.43% by weightof diluent(s)/binder(s), about 4% by weight of disintegrant(s), about 3%by weight of surfactant(s) and about 1% by weight of lubricant(s).

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 20-40% by weight of Compound A, about 30-50% by weightof cellulose, about 20-40% by weight of mannitol, about 1-10% by weightof carboxymethyl cellulose, about 1-10% by weight of hydroxypropylmethycellulose (HPMC) and about 0.1-2% by weight of magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 28.57% by weight of Compound A, about 37.43% by weightof cellulose, about 26% by weight of mannitol, about 4% by weight ofcarboxymethyl cellulose, about 3% by weight of HPMC and about 1% byweight of magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 20-40% by weight of Compound A, about 30-50% by weightof microcrystalline cellulose, about 20-40% by weight of mannitol, about1-10% by weight of carboxymethyl cellulose, about 1-10% by weight ofHPMC and about 0.1-2% by weight of magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 28.57% by weight of Compound A, about 37.43% by weightof microcrystalline cellulose, about 26% by weight of mannitol, about 4%by weight of carboxymethyl cellulose, about 3% by weight of HPMC andabout 1% by weight of magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 20-40% by weight of Compound A, about 30-50% by weightof AVICEL® PH 101 or AVICEL® PH 102, about 20-40% by weight of Mannitol200, about 1-10% by weight of AC-DI-SOL®, about 1-10% by weight ofMethocel™ K3 and about 0.1-2% by weight of magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 28.57% by weight of Compound A, about 37.43% by weightof AVICEL® PH 101 or AVICEL® PH 102, about 26% by weight of Mannitol200, about 4% by weight of AC-DI-SOL®, about 3% by weight of Methocel™K3 and about 1% by weight of magnesium stearate.

In one embodiment, the pharmaceutical composition further comprises acoating adding about 1-10% weight. In one embodiment, the pharmaceuticalcomposition further comprises a coating adding about 3% weight. In oneembodiment, the pharmaceutical composition further comprises a coatingcomprising Opadry and adding about 1-10% weight. In one embodiment, thepharmaceutical composition further comprises a coating comprising Opadryand adding about 3% weight. In one embodiment, the pharmaceuticalcomposition further comprises a coating comprising Opadry yellow, Opadrywhite or Opadry brown and adding about 1-10% weight. In one embodiment,the pharmaceutical composition further comprises a coating comprisingOpadry yellow, Opadry white or Opadry brown and adding about 3% weight.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 50-200 mg Compound A, about 100-400 mgdiluent(s)/binder(s), about 7-30 mg disintegrant(s), about 5-20 mgsurfactant(s) and about 0.1-10 mg lubricant(s).

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 100 mg Compound A, about 222 mg diluent(s)/binder(s),about 14 mg disintegrant(s), about 10.5 mg surfactant(s) and about 3.5mg lubricant(s).

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 50-200 mg Compound A, about 60-260 mg cellulose, about40-180 mg mannitol, about 7-30 mg carboxymethyl cellulose, about 5-20 mghydroxypropyl methycellulose (HPMC) and about 0.1-10 mg magnesiumstearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 100 mg Compound A, about 131.01 mg cellulose, about 91mg mannitol, about 14 mg carboxymethyl cellulose, about 10.5 mg HPMC andabout 3.5 mg magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 50-200 mg Compound A, about 60-260 mg microcrystallinecellulose, about 40-180 mg mannitol, about 7-30 mg carboxymethylcellulose, about 5-20 mg HPMC and about 0.1-10 mg magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 100 mg Compound A, about 131.01 mg microcrystallinecellulose, about 91 mg mannitol, about 14 mg carboxymethyl cellulose,about 10.5 mg HPMC and about 3.5 mg magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 50-200 mg Compound A, about 60-260 mg AVICEL® PH 101 orAVICEL® PH 102, about 40-180 mg Mannitol 200, about 7-30 mg AC-DI-SOL®,about 5-20 mg Methocel™ K3 and about 0.1-10 mg magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 100 mg Compound A, about 131.01 mg AVICEL® PH 101 orAVICEL® PH 102, about 91 mg Mannitol 200, about 14 mg AC-DI-SOL®, about10.5 mg Methocel™ K3 and about 3.5 mg magnesium stearate.

In one embodiment, the pharmaceutical composition further comprises acoating adding about 5-20 mg weight. In one embodiment, thepharmaceutical composition further comprises a coating adding about 10.5mg weight. In one embodiment, the pharmaceutical composition furthercomprises a coating comprising Opadry and adding about 5-20 mg weight.In one embodiment, the pharmaceutical composition further comprises acoating comprising Opadry and adding about 10.5 mg weight. In oneembodiment, the pharmaceutical composition further comprises a coatingcomprising Opadry yellow, Opadry white or Opadry brown and adding about5-20 mg weight. In one embodiment, the pharmaceutical compositionfurther comprises a coating comprising Opadry yellow, Opadry white orOpadry brown and adding about 10.5 mg weight.

In certain embodiments, provided herein are single unit dosage forms ofFormulation A. In particular embodiments, the single unit dosage formsare 30 mg, 100 mg or 200 mg tablets.

In one such embodiment, Compound A is Compound 1. In another embodiment,Compound A is a pharmaceutically acceptable salt of Compound 1. In yetanother embodiment, Compound A is a solid form of Compound 1.

5.5. Formulation B

In one embodiment, provided herein is a pharmaceutical compositioncomprising Compound A, and one or more pharmaceutically acceptableexcipients or carriers. In one embodiment, the pharmaceuticalcomposition is Formulation B comprising excipients or carriers describedin Table 4.

In one embodiment, provided herein is a pharmaceutical compositioncomprising Compound A and one or more pharmaceutically acceptableexcipients and carriers selected from diluents, surfactants,disintegrants and lubricants. In certain embodiments, the pharmaceuticalcompositions can be coated.

In certain embodiments, the diluents include, but are not limited to,mannitol (e.g., Mannitol 200), cellulose (e.g., microcrystallinecellulose, such as AVICEL® PH 101 and AVICEL® PH 102). In oneembodiment, the diluent is mannitol. In yet another embodiment, thediluent is Mannitol 200. In yet another embodiment, the diluent iscellulose. In yet another embodiment, the diluent is microcrystallinecellulose. In yet another embodiment, the diluent is AVICEL® PH 101. Instill another embodiment, the diluent is AVICEL® PH 102.

In certain embodiments, the surfactants include, but are not limited to,hydroxypropyl methycellulose (HPMC) (e.g., Methocel™ K3). In oneembodiment, the surfactant is Methocel™ K3.

In certain embodiments, the disintegrants include, but are not limitedto, carboxymethyl cellulose (e.g., croscarmellose sodium, such asAC-DI-SOL®). In one embodiment, the disintegrant is carboxymethylcellulose. In another embodiment, the disintegrant is croscarmellosesodium. In still another embodiment, the disintegrant is AC-DI-SOL®.

In one embodiment, the lubricant is magnesium stearate.

In certain embodiments, the coating includes, but is not limited to,Opadry (e.g., Opadry yellow, Opadry white and Opadry brown). In oneembodiment, the coating is Opadry. In another embodiment, the coating isOpadry yellow. In another embodiment, the coating is Opadry white. Inanother embodiment, the coating is Opadry brown.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A and one or more pharmaceutically acceptableexcipients or carriers, each independently selected from mannitol,cellulose, HPMC, carboxymethyl cellulose and magnesium stearate. Incertain embodiments, the pharmaceutical compositions are coated withOpadry.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A and one or more pharmaceutically acceptableexcipients or carriers, each independently selected from mannitol,microcrystalline cellulose, HPMC, croscarmellose sodium and magnesiumstearate. In certain embodiments, the pharmaceutical compositions arecoated with Opadry.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A and one or more pharmaceutically acceptableexcipients or carriers, each independently selected from Mannitol 200,AVICEL® PH 101, AVICEL® PH 102, Methocel™ K3, AC-DI-SOL® and magnesiumstearate. In certain embodiments, the pharmaceutical compositions arecoated with Opadry white, Opadry yellow or Opadry brown.

In one embodiment, provided herein is a pharmaceutical compositioncomprising Compound A, a diluent(s)/binder(s), a disintegrant(s), asurfactant(s) and a lubricant(s). In certain embodiments, thepharmaceutical compositions can be coated.

In one embodiment, provided herein is a pharmaceutical compositioncomprising Compound A, mannitol and magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising Compound A, mannitol, cellulose and magnesium stearate.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A, mannitol, microcrystalline cellulose,carboxymethyl cellulose and magnesium stearate.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A, mannitol, microcrystalline cellulose,croscarmellose sodium and magnesium stearate.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A, Mannitol 200, AVICEL® PH 101, AC-DI-SOL®,Methocel™ K3 and magnesium stearate.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A, Mannitol 200, AVICEL® PH 102, AC-DI-SOL®,Methocel™ K3 and magnesium stearate.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A, Mannitol 200, AVICEL® PH 101, AVICEL® PH 102,AC-DI-SOL®, Methocel™ K3 and magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 20-40% by weight of Compound A, about 50-70% by weightof diluent(s)/binder(s), about 1-20% by weight of disintegrant(s), about1-10% by weight of surfactant(s) and about 0.1-2% by weight oflubricant(s).

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 28.57% by weight of Compound A, about 59.43% by weightof diluent(s)/binder(s), about 8% by weight of disintegrant(s), about 3%by weight of surfactant(s) and about 1% by weight of lubricant(s).

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 20-40% by weight of Compound A, about 20-40% by weightof cellulose, about 20-40% by weight of mannitol, about 1-20% by weightof carboxymethyl cellulose, about 1-10% by weight of hydroxypropylmethycellulose (HPMC) and about 0.1-2% by weight of magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 28.57% by weight of Compound A, about 33.43% by weightof cellulose, about 26% by weight of mannitol, about 8% by weight ofcarboxymethyl cellulose, about 3% by weight of HPMC and about 1% byweight of magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 20-40% by weight of Compound A, about 20-40% by weightof microcrystalline cellulose, about 20-40% by weight of mannitol, about1-20% by weight of carboxymethyl cellulose, about 1-10% by weight ofHPMC and about 0.1-2% by weight of magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 28.57% by weight of Compound A, about 33.43% by weightof microcrystalline cellulose, about 26% by weight of mannitol, about 8%by weight of carboxymethyl cellulose, about 3% by weight of HPMC andabout 1% by weight of magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 20-40% by weight of Compound A, about 20-40% by weightof AVICEL® PH 101 or AVICEL® PH 102, about 20-40% by weight of Mannitol200, about 1-20% by weight of AC-DI-SOL®, about 1-10% by weight ofMethocel™ K3 and about 0.1-2% by weight of magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 28.57% by weight of Compound A, about 33.43% by weightof AVICEL® PH 101 or AVICEL® PH 102, about 26% by weight of Mannitol200, about 8% by weight of AC-DI-SOL®, about 3% by weight of Methocel™K3 and about 1% by weight of magnesium stearate.

In one embodiment, the pharmaceutical composition further comprises acoating adding about 1-10% weight. In one embodiment, the pharmaceuticalcomposition further comprises a coating adding about 3% weight. In oneembodiment, the pharmaceutical composition further comprises a coatingcomprising Opadry and adding about 1-10% weight. In one embodiment, thepharmaceutical composition further comprises a coating comprising Opadryand adding about 3% weight. In one embodiment, the pharmaceuticalcomposition further comprises a coating comprising Opadry yellow, Opadrywhite or Opadry brown and adding about 1-10% weight. In one embodiment,the pharmaceutical composition further comprises a coating comprisingOpadry yellow, Opadry white or Opadry brown and adding about 3% weight.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 50-200 mg Compound A, about 100-400 mgdiluent(s)/binder(s), about 10-60 mg disintegrant(s), about 5-20 mgsurfactant(s) and about 0.1-10 mg lubricant(s).

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 100 mg Compound A, about 208.1 mg diluent(s)/binder(s),about 28 mg disintegrant(s), about 10.5 mg surfactant(s) and about 3.5mg lubricant(s).

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 50-200 mg Compound A, about 60-240 mg cellulose, about40-180 mg mannitol, about 10-60 mg carboxymethyl cellulose, about 5-20mg hydroxypropyl methycellulose (HPMC) and about 0.1-10 mg magnesiumstearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 100 mg Compound A, about 117.1 mg cellulose, about 91mg mannitol, about 28 mg carboxymethyl cellulose, about 10.5 mg HPMC andabout 3.5 mg magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 50-200 mg Compound A, about 60-240 mg microcrystallinecellulose, about 40-180 mg mannitol, about 10-60 mg carboxymethylcellulose, about 5-20 mg HPMC and about 0.1-10 mg magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 100 mg Compound A, about 117.1 mg microcrystallinecellulose, about 91 mg mannitol, about 28 mg carboxymethyl cellulose,about 10.5 mg HPMC and about 3.5 mg magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 50-200 mg Compound A, about 60-240 mg AVICEL® PH 101 orAVICEL® PH 102, about 40-180 mg Mannitol 200, about 10-60 mg AC-DI-SOL®,about 5-20 mg Methocel™ K3 and about 0.1-10 mg magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 100 mg Compound A, about 117.1 mg AVICEL® PH 101 orAVICEL® PH 102, about 91 mg Mannitol 200, about 28 mg AC-DI-SOL®, about10.5 mg Methocel™ K3 and about 3.5 mg magnesium stearate.

In one embodiment, the pharmaceutical composition further comprises acoating adding about 5-20 mg weight. In one embodiment, thepharmaceutical composition further comprises a coating adding about 10.5mg weight. In one embodiment, the pharmaceutical composition furthercomprises a coating comprising Opadry and adding about 5-20 mg weight.In one embodiment, the pharmaceutical composition further comprises acoating comprising Opadry and adding about 10.5 mg weight. In oneembodiment, the pharmaceutical composition further comprises a coatingcomprising Opadry yellow, Opadry white or Opadry brown and adding about5-20 mg weight. In one embodiment, the pharmaceutical compositionfurther comprises a coating comprising Opadry yellow, Opadry white orOpadry brown and adding about 10.5 mg weight.

In certain embodiments, provided herein are single unit dosage forms ofFormulation B. In particular embodiments, the single unit dosage formsare 30 mg, 100 mg or 200 mg tablets.

In one such embodiment, Compound A is Compound 1. In another embodiment,Compound A is a pharmaceutically acceptable salt of Compound 1. In yetanother embodiment, Compound A is a solid form of Compound 1.

5.6. Formulation C

In one embodiment, provided herein is a pharmaceutical compositioncomprising Compound A, and one or more pharmaceutically acceptableexcipients or carriers. In one embodiment, the pharmaceuticalcomposition is Formulation C comprising excipients or carriers describedin Table 5.

In one embodiment, provided herein is a pharmaceutical compositioncomprising Compound A and one or more pharmaceutically acceptableexcipients and carriers selected from diluents, surfactants,disintegrants and lubricants. In certain embodiments, the pharmaceuticalcompositions can be coated.

In certain embodiments, the diluents include, but are not limited to,mannitol (e.g., Mannitol 200), cellulose (e.g., microcrystallinecellulose, such as AVICEL® PH 101 and AVICEL® PH 102). In oneembodiment, the diluent is mannitol. In yet another embodiment, thediluent is Mannitol 200. In yet another embodiment, the diluent iscellulose. In yet another embodiment, the diluent is microcrystallinecellulose. In yet another embodiment, the diluent is AVICEL® PH 101. Instill another embodiment, the diluent is AVICEL® PH 102.

In certain embodiments, the surfactants include, but are not limited to,hydroxypropyl methycellulose (HPMC) (e.g., Methocel™ K3). In oneembodiment, the surfactant is Methocel™ K3.

In certain embodiments, the disintegrants include, but are not limitedto, carboxymethyl cellulose (e.g., croscarmellose sodium, such asAC-DI-SOL®). In one embodiment, the disintegrant is carboxymethylcellulose. In another embodiment, the disintegrant is croscarmellosesodium. In still another embodiment, the disintegrant is AC-DI-SOL®.

In one embodiment, the lubricant is magnesium stearate.

In certain embodiments, the coating includes, but is not limited to,Opadry (e.g., Opadry yellow, Opadry white and Opadry brown). In oneembodiment, the coat is Opadry. In another embodiment, the coat isOpadry yellow. In another embodiment, the coat is Opadry white. Inanother embodiment, the coat is Opadry brown.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A and one or more pharmaceutically acceptableexcipients or carriers, each independently selected from mannitol,cellulose, HPMC, carboxymethyl cellulose and magnesium stearate. Incertain embodiments, the pharmaceutical compositions are coated withOpadry.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A and one or more pharmaceutically acceptableexcipients or carriers, each independently selected from mannitol,microcrystalline cellulose, HPMC, croscarmellose sodium and magnesiumstearate. In certain embodiments, the pharmaceutical compositions arecoated with Opadry.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A and one or more pharmaceutically acceptableexcipients or carriers, each independently selected from Mannitol 200,AVICEL® PH 101, AVICEL® PH 102, Methocel™ K3, AC-DI-SOL® and magnesiumstearate. In certain embodiments, the pharmaceutical compositions arecoated with Opadry white, Opadry yellow or Opadry brown.

In one embodiment, provided herein is a pharmaceutical compositioncomprising Compound A, a diluent(s)/binder(s), a disintegrant(s), asurfactant(s) and a lubricant(s). In certain embodiments, thepharmaceutical compositions can be coated.

In one embodiment, provided herein is a pharmaceutical compositioncomprising Compound A, mannitol and magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising Compound A, mannitol, cellulose and magnesium stearate.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A, mannitol, microcrystalline cellulose,carboxymethyl cellulose and magnesium stearate.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A, mannitol, microcrystalline cellulose,croscarmellose sodium and magnesium stearate.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A, Mannitol 200, AVICEL® PH 101, AC-DI-SOL®,Methocel™ K3 and magnesium stearate.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A, Mannitol 200, AVICEL® PH 102, AC-DI-SOL®,Methocel™ K3 and magnesium stearate.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A, Mannitol 200, AVICEL® PH 101, AVICEL® PH 102,AC-DI-SOL®, Methocel™ K3 and magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 20-40% by weight of Compound A, about 50-70% by weightof diluent(s)/binder(s), about 1-20% by weight of disintegrant(s), about1-10% by weight of surfactant(s) and about 0.1-2% by weight oflubricant(s).

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 28.57% by weight of Compound A, about 57.93% by weightof diluent(s)/binder(s), about 8% by weight of disintegrant(s), about4.5% by weight of surfactant(s) and about 1% by weight of lubricant(s).

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 20-40% by weight of Compound A, about 20-40% by weightof cellulose, about 20-40% by weight of mannitol, about 1-20% by weightof carboxymethyl cellulose, about 1-10% by weight of hydroxypropylmethycellulose (HPMC) and about 0.1-2% by weight of magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 28.57% by weight of Compound A, about 31.93% by weightof cellulose, about 26% by weight of mannitol, about 8% by weight ofcarboxymethyl cellulose, about 4.5% by weight of HPMC and about 1% byweight of magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 20-40% by weight of Compound A, about 20-40% by weightof microcrystalline cellulose, about 20-40% by weight of mannitol, about1-20% by weight of carboxymethyl cellulose, about 1-10% by weight ofHPMC and about 0.1-2% by weight of magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 28.57% by weight of Compound A, about 31.93% by weightof microcrystalline cellulose, about 26% by weight of mannitol, about 8%by weight of carboxymethyl cellulose, about 4.5% by weight of HPMC andabout 1% by weight of magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 20-40% by weight of Compound A, about 20-40% by weightof AVICEL® PH 101 or AVICEL® PH 102, about 20-40% by weight of Mannitol200, about 1-20% by weight of AC-DI-SOL®, about 1-10% by weight ofMethocel™ K3 and about 0.1-2% by weight of magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 28.57% by weight of Compound A, about 31.93% by weightof AVICEL® PH 101 or AVICEL® PH 102, about 26% by weight of Mannitol200, about 8% by weight of AC-DI-SOL®, about 4.5% by weight of Methocel™K3 and about 1% by weight of magnesium stearate.

In one embodiment, the pharmaceutical composition further comprises acoating adding about 1-10% weight. In one embodiment, the pharmaceuticalcomposition further comprises a coating adding about 3% weight. In oneembodiment, the pharmaceutical composition further comprises a coatingcomprising Opadry and adding about 1-10% weight. In one embodiment, thepharmaceutical composition further comprises a coating comprising Opadryand adding about 3% weight. In one embodiment, the pharmaceuticalcomposition further comprises a coating comprising Opadry yellow, Opadrywhite or Opadry brown and adding about 1-10% weight. In one embodiment,the pharmaceutical composition further comprises a coating comprisingOpadry yellow, Opadry white or Opadry brown and adding about 3% weight.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 50-200 mg Compound A, about 100-400 mgdiluent(s)/binder(s), about 10-60 mg disintegrant(s), about 5-30 mgsurfactant(s) and about 0.1-10 mg lubricant(s).

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 100 mg Compound A, about 202.76 mgdiluent(s)/binder(s), about 28 mg disintegrant(s), about 15.75 mgsurfactant(s) and about 3.5 mg lubricant(s).

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 50-200 mg Compound A, about 50-220 mg cellulose, about40-180 mg mannitol, about 10-60 mg carboxymethyl cellulose, about 5-30mg hydroxypropyl methycellulose (HPMC) and about 0.1-10 mg magnesiumstearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 100 mg Compound A, about 111.76 mg cellulose, about 91mg mannitol, about 28 mg carboxymethyl cellulose, about 15.75 mg HPMCand about 3.5 mg magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 50-200 mg Compound A, about 50-220 mg microcrystallinecellulose, about 40-180 mg mannitol, about 10-60 mg carboxymethylcellulose, about 5-30 mg HPMC and about 0.1-10 mg magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 100 mg Compound A, about 111.76 mg microcrystallinecellulose, about 91 mg mannitol, about 28 mg carboxymethyl cellulose,about 15.75 mg HPMC and about 3.5 mg magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 50-200 mg Compound A, about 50-220 mg AVICEL® PH 101 orAVICEL® PH 102, about 40-180 mg Mannitol 200, about 10-60 mg AC-DI-SOL®,about 5-30 mg Methocel™ K3 and about 0.1-10 mg magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 100 mg Compound A, about 111.76 mg AVICEL® PH 101 orAVICEL® PH 102, about 91 mg Mannitol 200, about 28 mg AC-DI-SOL®, about15.75 mg Methocel™ K3 and about 3.5 mg magnesium stearate.

In one embodiment, the pharmaceutical composition further comprises acoating adding about 5-20 mg weight. In one embodiment, thepharmaceutical composition further comprises a coating adding about 10.5mg weight. In one embodiment, the pharmaceutical composition furthercomprises a coating comprising Opadry and adding about 5-20 mg weight.In one embodiment, the pharmaceutical composition further comprises acoating comprising Opadry and adding about 10.5 mg weight. In oneembodiment, the pharmaceutical composition further comprises a coatingcomprising Opadry yellow, Opadry white or Opadry brown and adding about5-20 mg weight. In one embodiment, the pharmaceutical compositionfurther comprises a coating comprising Opadry yellow, Opadry white orOpadry brown and adding about 10.5 mg weight.

In certain embodiments, provided herein are single unit dosage forms ofFormulation C. In particular embodiments, the single unit dosage formsare 30 mg, 100 mg or 200 mg tablets.

In one such embodiment, Compound A is Compound 1. In another embodiment,Compound A is a pharmaceutically acceptable salt of Compound 1. In yetanother embodiment, Compound A is a solid form of Compound 1.

5.7. Formulation D

In one embodiment, provided herein is a pharmaceutical compositioncomprising Compound A, and one or more pharmaceutically acceptableexcipients or carriers. In one embodiment, the pharmaceuticalcomposition is Formulation C comprising excipients or carriers describedin Table 6.

In one embodiment, provided herein is a pharmaceutical compositioncomprising Compound A and one or more pharmaceutically acceptableexcipients and carriers selected from diluents, surfactants,disintegrants and lubricants. In certain embodiments, the pharmaceuticalcompositions can be coated.

In certain embodiments, the diluents include, but are not limited to,mannitol (e.g., Mannitol 200), cellulose (e.g., microcrystallinecellulose, such as AVICEL® PH 101 and AVICEL® PH 102). In oneembodiment, the diluent is mannitol. In yet another embodiment, thediluent is Mannitol 200. In yet another embodiment, the diluent iscellulose. In yet another embodiment, the diluent is microcrystallinecellulose. In yet another embodiment, the diluent is AVICEL® PH 101. Instill another embodiment, the diluent is AVICEL® PH 102.

In certain embodiments, the surfactants include, but are not limited to,hydroxypropyl methycellulose (HPMC) (e.g., Methocel™ K3). In oneembodiment, the surfactant is Methocel™ K3.

In certain embodiments, the disintegrants include, but are not limitedto, carboxymethyl cellulose (e.g., croscarmellose sodium, such asAC-DI-SOL®). In one embodiment, the disintegrant is carboxymethylcellulose. In another embodiment, the disintegrant is croscarmellosesodium. In still another embodiment, the disintegrant is AC-DI-SOL®.

In one embodiment, the lubricant is magnesium stearate.

In certain embodiments, the coating includes, but is not limited to,Opadry (e.g., Opadry yellow, Opadry white and Opadry brown). In oneembodiment, the coat is Opadry. In another embodiment, the coat isOpadry yellow. In another embodiment, the coat is Opadry white. Inanother embodiment, the coat is Opadry brown.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A and one or more pharmaceutically acceptableexcipients or carriers, each independently selected from mannitol,cellulose, HPMC, carboxymethyl cellulose and magnesium stearate. Incertain embodiments, the pharmaceutical compositions are coated withOpadry.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A and one or more pharmaceutically acceptableexcipients or carriers, each independently selected from mannitol,microcrystalline cellulose, HPMC, croscarmellose sodium and magnesiumstearate. In certain embodiments, the pharmaceutical compositions arecoated with Opadry.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A and one or more pharmaceutically acceptableexcipients or carriers, each independently selected from Mannitol 200,AVICEL® PH 101, AVICEL® PH 102, Methocel™ K3, AC-DI-SOL® and magnesiumstearate. In certain embodiments, the pharmaceutical compositions arecoated with Opadry white, Opadry yellow or Opadry brown.

In one embodiment, provided herein is a pharmaceutical compositioncomprising Compound A, a diluent(s)/binder(s), a disintegrant(s), asurfactant(s) and a lubricant(s). In certain embodiments, thepharmaceutical compositions can be coated.

In one embodiment, provided herein is a pharmaceutical compositioncomprising Compound A, mannitol and magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising Compound A, mannitol, cellulose and magnesium stearate.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A, mannitol, microcrystalline cellulose,carboxymethyl cellulose and magnesium stearate.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A, mannitol, microcrystalline cellulose,croscarmellose sodium and magnesium stearate.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A, Mannitol 200, AVICEL® PH 101, AC-DI-SOL®,Methocel™ K3 and magnesium stearate.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A, Mannitol 200, AVICEL® PH 102, AC-DI-SOL®,Methocel™ K3 and magnesium stearate.

In certain embodiments, provided herein are pharmaceutical compositionscomprising Compound A, Mannitol 200, AVICEL® PH 101, AVICEL® PH 102,AC-DI-SOL®, Methocel™ K3 and magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 20-40% by weight of Compound A, about 50-70% by weightof diluent(s)/binder(s), about 1-10% by weight of disintegrant(s), about1-10% by weight of surfactant(s) and about 0.1-2% by weight oflubricant(s).

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 28.57% by weight of Compound A, about 61.93% by weightof diluent(s)/binder(s), about 4% by weight of disintegrant(s), about4.5% by weight of surfactant(s) and about 1% by weight of lubricant(s).

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 20-40% by weight of Compound A, about 20-50% by weightof cellulose, about 20-40% by weight of mannitol, about 1-10% by weightof carboxymethyl cellulose, about 1-10% by weight of hydroxypropylmethycellulose (HPMC) and about 0.1-2% by weight of magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 28.57% by weight of Compound A, about 35.93% by weightof cellulose, about 26% by weight of mannitol, about 4% by weight ofcarboxymethyl cellulose, about 4.5% by weight of HPMC and about 1% byweight of magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 20-40% by weight of Compound A, about 20-50% by weightof microcrystalline cellulose, about 20-40% by weight of mannitol, about1-10% by weight of carboxymethyl cellulose, about 1-10% by weight ofHPMC and about 0.1-2% by weight of magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 28.57% by weight of Compound A, about 35.93% by weightof microcrystalline cellulose, about 26% by weight of mannitol, about 4%by weight of carboxymethyl cellulose, about 4.5% by weight of HPMC andabout 1% by weight of magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 20-40% by weight of Compound A, about 20-50% by weightof AVICEL® PH 101 or AVICEL® PH 102, about 20-40% by weight of Mannitol200, about 1-10% by weight of AC-DI-SOL®, about 1-10% by weight ofMethocel™ K3 and about 0.1-2% by weight of magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 28.57% by weight of Compound A, about 35.93% by weightof AVICEL® PH 101 or AVICEL® PH 102, about 26% by weight of Mannitol200, about 4% by weight of AC-DI-SOL®, about 4.5% by weight of Methocel™K3 and about 1% by weight of magnesium stearate.

In one embodiment, the pharmaceutical composition further comprises acoating adding about 1-10% weight. In one embodiment, the pharmaceuticalcomposition further comprises a coating adding about 3% weight. In oneembodiment, the pharmaceutical composition further comprises a coatingcomprising Opadry and adding about 1-10% weight. In one embodiment, thepharmaceutical composition further comprises a coating comprising Opadryand adding about 3% weight. In one embodiment, the pharmaceuticalcomposition further comprises a coating comprising Opadry yellow, Opadrywhite or Opadry brown and adding about 1-10% weight. In one embodiment,the pharmaceutical composition further comprises a coating comprisingOpadry yellow, Opadry white or Opadry brown and adding about 3% weight.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 50-200 mg Compound A, about 100-400 mgdiluent(s)/binder(s), about 7-30 mg disintegrant(s), about 5-30 mgsurfactant(s) and about 0.1-10 mg lubricant(s).

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 100 mg Compound A, about 216.76 mgdiluent(s)/binder(s), about 14 mg disintegrant(s), about 15.75 mgsurfactant(s) and about 3.5 mg lubricant(s).

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 50-200 mg Compound A, about 60-240 mg cellulose, about40-180 mg mannitol, about 7-30 mg carboxymethyl cellulose, about 5-30 mghydroxypropyl methycellulose (HPMC) and about 0.1-10 mg magnesiumstearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 100 mg Compound A, about 125.76 mg cellulose, about 91mg mannitol, about 14 mg carboxymethyl cellulose, about 15.75 mg HPMCand about 3.5 mg magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 50-200 mg Compound A, about 60-240 mg microcrystallinecellulose, about 40-180 mg mannitol, about 7-30 mg carboxymethylcellulose, about 5-30 mg HPMC and about 0.1-10 mg magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 100 mg Compound A, about 125.76 mg microcrystallinecellulose, about 91 mg mannitol, about 14 mg carboxymethyl cellulose,about 15.75 mg HPMC and about 3.5 mg magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 50-200 mg Compound A, about 60-240 mg AVICEL® PH 101 orAVICEL® PH 102, about 40-180 mg Mannitol 200, about 7-30 mg AC-DI-SOL®,about 5-30 mg Methocel™ K3 and about 0.1-10 mg magnesium stearate.

In one embodiment, provided herein is a pharmaceutical compositioncomprising about 100 mg Compound A, about 125.76 mg AVICEL® PH 101 orAVICEL® PH 102, about 91 mg Mannitol 200, about 14 mg AC-DI-SOL®, about15.75 mg Methocel™ K3 and about 3.5 mg magnesium stearate.

In one embodiment, the pharmaceutical composition further comprises acoating adding about 5-20 mg weight. In one embodiment, thepharmaceutical composition further comprises a coating adding about 10.5mg weight. In one embodiment, the pharmaceutical composition furthercomprises a coating comprising Opadry and adding about 5-20 mg weight.In one embodiment, the pharmaceutical composition further comprises acoating comprising Opadry and adding about 10.5 mg weight. In oneembodiment, the pharmaceutical composition further comprises a coatingcomprising Opadry yellow, Opadry white or Opadry brown and adding about5-20 mg weight. In one embodiment, the pharmaceutical compositionfurther comprises a coating comprising Opadry yellow, Opadry white orOpadry brown and adding about 10.5 mg weight.

In certain embodiments, provided herein are single unit dosage forms ofFormulation D. In particular embodiments, the single unit dosage formsare 30 mg, 100 mg or 200 mg tablets.

In one such embodiment, Compound A is Compound 1. In another embodiment,Compound A is a pharmaceutically acceptable salt of Compound 1. In yetanother embodiment, Compound A is a solid form of Compound 1.

5.8. Methods of Use

Pharmaceutical compositions, and dosage forms of Compound A have utilityas pharmaceuticals to treat, prevent or improve conditions in animals orhumans. Compound A is active against protein kinases, particularly JNK1and/or JNK2. Accordingly, provided herein are many uses ofpharmaceutical compositions, dosage forms and salts of Compound A,including the treatment or prevention of those diseases set forth below.The methods provided herein comprise the administration of apharmaceutical composition, and dosage form of Compound A to a subjectin need thereof. In one aspect, provided herein are methods ofinhibiting a kinase in a cell expressing said kinase, comprisingcontacting said cell with an effective amount of a pharmaceuticalcomposition, and dosage form of Compound A. In one embodiment, thekinase is JNK1, JNK2, or a mutant or isoform thereof, or a combinationthereof.

In another aspect, provided herein are methods for treating orpreventing one or more disorders selected from interstitial pulmonaryfibrosis, systemic sclerosis, scleroderma, chronic allograftnephropathy, antibody mediated rejection, or lupus, comprisingadministering to a subject in need thereof an effective amount of apharmaceutical composition, or dosage form of Compound A. In some suchembodiments, the lupus is lupus erythematosus (such as discoid lupuserythematosus, or cutaneous lupus erythematosus) or systemic lupus. Insome embodiments, the disorder is pulmonary fibrosis. In someembodiments, the pulmonary fibrosis is a documented usual interstitialpneumonia (UIP) pattern or nonspecific interstitial pneumonia (NSIP)pattern, for example, based on computed tomography or a documentedfibrotic NSIP or documented UIP pattern, for example, based on surgicallung biopsy. In some embodiments, the underlying disease of thepulmonary fibrosis is connective tissue disease-associated interstitiallung disease, interstitial pulmonary fibrosis, idiopathic pulmonaryfibrosis (IPF), environmental- or chemical-related pulmonary fibrosis,or Hermansky-Pudlak syndrome.

In another aspect, provided herein are methods for treating orpreventing liver fibrotic disorders, such as non-alcoholicsteatohepatitis, steatosis (i.e. fatty liver), cirrhosis, primarysclerosing cholangitis, primary biliary cirrhosis, hepatitis,hepatocellular carcinoma, and liver fibrosis coincident with chronic orrepeated alcohol ingestion (alcoholic hepatitis), with infection (e.g.,viral infection such as HCV), with liver transplant, or with druginduced liver injury (e.g., acetaminophen toxicity), comprisingadministering to a subject in need thereof an effective amount of apharmaceutical composition, or dosage form of Compound A. In some suchaspects, provided herein are methods for treating or preventing diabetesor metabolic syndrome leading to liver fibrotic disorders, such asnon-alcoholic steatohepatitis, steatosis (i.e. fatty liver), cirrhosis,primary sclerosing cholangitis, primary biliary cirrhosis, andhepatitis, comprising administering to a subject in need thereof aneffective amount of a pharmaceutical composition, or dosage form ofCompound A.

In another aspect, provided herein are methods for treating orpreventing conditions treatable or preventable by inhibition of JNK1and/or JNK2, the method comprising administering to a subject in needthereof an effective amount of a pharmaceutical composition, or dosageform of Compound A. Examples of such conditions include rheumatoidarthritis, rheumatoid spondylitis, osteoarthritis, asthma, bronchitis,allergic rhinitis, chronic obstructive pulmonary disease, cysticfibrosis, inflammatory bowel disease, irritable bowel syndrome, mucouscolitis, ulcerative colitis, Crohn's disease, Huntington's disease,hepatitis, pancreatitis, nephritis, multiple sclerosis, lupuserythematosus, Type II diabetes, obesity, atherosclerosis, restenosisfollowing angioplasty, left ventricular hypertrophy, myocardialinfarction, stroke, ischemic damages of heart, lung, gut, kidney, liver,pancreas, spleen and brain, acute or chronic organ transplant rejection,preservation of the organ for transplantation, organ failure or loss oflimb (e.g., including, but not limited to, that resulting fromischemia-reperfusion injury, trauma, gross bodily injury, car accident,crush injury or transplant failure), graft versus host disease,endotoxin shock, multiple organ failure, psoriasis, burn from exposureto fire, chemicals or radiation, eczema, dermatitis, skin graft,ischemia, ischemic conditions associated with surgery or traumaticinjury (e.g., vehicle accident, gunshot wound or limb crush), epilepsy,Alzheimer's disease, Parkinson's disease, immunological response tobacterial or viral infection, cachexia, angiogenic and proliferativediseases, solid tumor, and cancers of a variety of tissues such ascolon, rectum, prostate, liver, lung, bronchus, pancreas, brain, head,neck, stomach, skin, kidney, cervix, blood, larynx, esophagus, mouth,pharynx, urinary bladder, ovary or uterine.

In one embodiment, provided herein are methods for modulating the levelsof a disease marker in a subject having a JNK1 and/or JNK2-mediateddisorder, comprising administering an effective amount of Compound A ora pharmaceutical composition provided herein, to said subject. In someembodiments, the JNK1 and/or JNK2-mediated disorder is pulmonaryfibrosis. In some such embodiments, the modulation of the disease markeris assessed in a biological sample of the subject, such as incirculating blood, skin biopsies, colon biopsies, synovial tissue,and/or urine. In such embodiments, the amount of disease markermodulation is assessed by comparison of the amount of disease markerbefore and after administration of Compound A. In some embodiments, themodulation in disease biomarker is a reduction about 5%, 10%, 20%, 25%,30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 99%, or about 100% comparedto baseline levels. In some embodiments, the disease marker is mRNA orprotein levels of one or more of matrix metalloproteinase-7, Tenascin C,or Surfactant Protein-D.

In one such embodiment, Compound A is Compound 1. In another embodiment,Compound A is a pharmaceutically acceptable salt of Compound 1. In yetanother embodiment, Compound A is a solid form of Compound 1.

5.9. Routes of Administration and Dosage

Pharmaceutical compositions, and dosage forms of Compound A can beadministered to a subject orally, topically or parenterally in theconventional form of preparations, such as tablets, granules, powder,troches, pills, suppositories, injections, suspensions, syrups, patches,creams, lotions, ointments, gels, sprays, solutions and emulsions. Theeffective amount of Compound A in the pharmaceutical composition may beat a level that will exercise the desired effect; for example, about0.005 mg/kg of a subject's body weight to about 10 mg/kg of a subject'sbody weight in unit dosage for both oral and parenteral administration.

The dose of Compound A to be administered to a subject is rather widelyvariable and can be subject to the judgment of a healthcarepractitioner. In general, Compound A can be administered one to fourtimes a day in a dose of about 0.005 mg/kg of a subject's body weight toabout 10 mg/kg of a subject's body weight in a subject, but the abovedosage may be properly varied depending on the age, body weight andmedical condition of the subject and the type of administration. In oneembodiment, the dose is about 0.01 mg/kg of a subject's body weight toabout 5 mg/kg of a subject's body weight, about 0.05 mg/kg of asubject's body weight to about 1 mg/kg of a subject's body weight, about0.1 mg/kg of a subject's body weight to about 0.75 mg/kg of a subject'sbody weight or about 0.25 mg/kg of a subject's body weight to about 0.5mg/kg of a subject's body weight. In one embodiment, one dose is givenper day. In any given case, the amount of Compound A administered willdepend on such factors as the solubility of the active component, theformulation used and the route of administration. In one embodiment,application of a topical concentration provides intracellular exposuresor concentrations of about 0.01-10 μM.

In another embodiment, provided herein are methods for the treatment orprevention of a disease or disorder comprising the administration of apharmaceutical composition, or dosage form comprising about 0.375 mg/dayto about 750 mg/day, about 0.75 mg/day to about 375 mg/day, about 3.75mg/day to about 75 mg/day, about 7.5 mg/day to about 55 mg/day or about18 mg/day to about 37 mg/day of Compound A to a subject in need thereof.

In another embodiment, provided herein are methods for the treatment orprevention of a disease or disorder comprising the administration of apharmaceutical composition, or dosage form comprising about 1 mg/day toabout 1200 mg/day, about 10 mg/day to about 1200 mg/day, about 100mg/day to about 1200 mg/day, about 400 mg/day to about 1200 mg/day,about 600 mg/day to about 1200 mg/day, about 400 mg/day to about 800mg/day, about 60 mg/day to about 720 mg/day, about 240 mg/day to about720 mg/day or about 600 mg/day to about 800 mg/day of Compound A to asubject in need thereof. In a particular embodiment, the methodsdisclosed herein comprise the administration of a pharmaceuticalcomposition, or dosage form comprising about 400 mg/day, about 600mg/day or about 800 mg/day of Compound A to a subject in need thereof.

In another embodiment, provided herein are methods for the treatment orprevention of a disease or disorder comprising the administration of apharmaceutical composition, or dosage form comprising about 10 mg/day toabout 720 mg/day, about 10 mg/day to about 480 mg/day, about 60 mg/dayto about 720 mg/day or about 240 mg/day to about 720 mg/day of CompoundA to a subject in need thereof.

In one embodiment, provided herein are methods for the treatment orprevention of a disease or disorder comprising the administration of apharmaceutical composition, or dosage form comprising about 10 mg/day,about 30 mg/day, about 60 mg/day, about 100 mg/day, about 120 mg/day,about 240 mg/day, about 480 mg/day, or about 720 mg/day of Compound A toa subject in need thereof. In one embodiment, provided herein aremethods for the treatment or prevention of a disease or disordercomprising the administration of a pharmaceutical composition, or dosageform comprising about 60 mg/day, about 160 mg/day, or about 400 mg/dayof Compound A to a subject in need thereof. In one embodiment, providedherein are methods for the treatment or prevention of a disease ordisorder comprising the administration of a pharmaceutical composition,or dosage form comprising about 100 mg/day, or about 200 mg/day ofCompound A to a subject in need thereof. In another embodiment, providedherein are methods for the treatment or prevention of a disease ordisorder comprising the administration of a pharmaceutical composition,or dosage form comprising about 100 mg/day of Compound A to a subject inneed thereof. In another embodiment, provided herein are methods for thetreatment or prevention of a disease or disorder comprising theadministration of a pharmaceutical composition, or dosage formcomprising about 200 mg/day of Compound A to a subject in need thereof.In one embodiment, provided herein are methods for the treatment orprevention of a disease or disorder comprising the administration of apharmaceutical composition, or dosage form comprising about 10 mg/day,about 30 mg/day, about 60 mg/day, about 120 mg/day, about 160 mg/day,about 200 mg/day, about 240 mg/day, about 400 mg/day, about 480 mg/day,or about 720 mg/day of Compound A to a subject in need thereof.

In another embodiment, provided herein are unit dosage formulations thatcomprise between about 10 mg and about 100 mg, about 1 mg and about 200mg, about 30 mg and about 200 mg, about 35 mg and about 1400 mg, about125 mg and about 1000 mg, about 250 mg and about 1000 mg, or about 500mg and about 1000 mg of Compound A.

In another embodiment, provided herein are unit dosage formulations thatcomprise about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg,about 30 mg, about 35 mg, about 50 mg, about 60 mg, about 70 mg, about100 mg, about 120 mg, about 125 mg, about 140 mg, about 175 mg, about200 mg, about 240 mg, about 250 mg, about 280 mg, about 350 mg, about480 mg, about 500 mg, about 560 mg, about 700 mg, about 720 mg, about750 mg, about 1000 mg or about 1400 mg of Compound A.

In another embodiment, provided herein are unit dosage forms thatcomprise about 30 mg, about 100 mg or about 200 mg of Compound A.

Pharmaceutical compositions, and dosage forms of Compound A can beadministered once, twice, three, four or more times daily. In oneembodiment, pharmaceutical compositions, and dosage forms of Compound Acan be administered once daily for 14 days.

Pharmaceutical compositions, and dosage forms of Compound A can beadministered orally for reasons of convenience. In one embodiment, whenadministered orally, pharmaceutical compositions, and dosage forms ofCompound A are administered with a meal and water. In anotherembodiment, pharmaceutical compositions, and dosage forms of Compound A(e.g., granules or dispersible tablets) are dispersed in water or juice(e.g., apple juice or orange juice) and administered orally as asuspension.

Pharmaceutical compositions, and dosage forms of Compound A can also beadministered intradermally, intramuscularly, intraperitoneally,percutaneously, intravenously, subcutaneously, intranasally, epidurally,sublingually, intracerebrally, intravaginally, transdermally, rectally,mucosally, by inhalation, or topically to the ears, nose, eyes, or skin.The mode of administration is left to the discretion of the health-carepractitioner, and can depend in-part upon the site of the medicalcondition.

In one such embodiment, Compound A is Compound 1. In another embodiment,Compound A is a pharmaceutically acceptable salt of Compound 1. In yetanother embodiment, Compound A is a solid form of Compound 1.

5.10. Process for Making Dosage Forms

Dosage forms provided herein can be prepared by any of the methods ofpharmacy, but all methods include the step of bringing the activeingredient into association with the excipient, which constitutes one ormore necessary ingredients. In general, the compositions are prepared byuniformly admixing (e.g., direct blend) the active ingredient withliquid excipients or finely divided solid excipients or both, and then,if necessary, shaping the product into the desired presentation (e.g.,compaction such as roller-compaction). If desired, tablets can be coatedby standard aqueous or non-aqueous techniques.

A dosage form provided herein can be prepared by compression or molding,optionally with one or more accessory ingredients. Compressed tabletscan be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with an excipient as above and/or a surface active or dispersingagent. Molded tablets can be made by molding in a suitable machine amixture of the powdered compound moistened with an inert liquid diluent.

In some embodiments, the active ingredients and excipients are directlyblended and compressed directly into tablets. A direct-blended dosageform may be more advantageous than a compacted (e.g., roller-compacted)dosage form in certain instances, since direct-blending can reduce oreliminate the harmful health effects that may be caused by airborneparticles of ingredients during the manufacture using compactionprocess.

Direct blend formulations may be advantageous in certain instancesbecause they require only one blending step, that of the active andexcipients, before being processed into the final dosage form, e.g.,tablet. This can reduce the production of airborne particle or dust to aminimum, while roller-compaction processes may be prone to produce dust.In roller-compaction process, the compacted material is often milledinto smaller particles for further processing. The milling operation canproduce significant amounts of airborne particles, since the purpose forthis step in manufacturing is to reduce the materials particle size. Themilled material is then blended with other ingredients prior tomanufacturing the final dosage form.

For certain active ingredients, in particular for a compound with a lowsolubility, the active ingredient's particle size is reduced to a finepowder in order to help increase the active ingredient's rate ofsolubilization. The increase in the rate of solubilization is oftennecessary for the active ingredient to be effectively absorbed in thegastrointestinal tract. However for fine powders to be directly-blendedand compressed to tablets, the excipients should preferably providecertain characteristics which render the ingredients suitable for thedirect-blend process. Examples of such characteristics include, but arenot limited to, acceptable flow characteristics. In one embodiment,therefore, provided herein is the use of, and compositions comprising,excipients which may provide characteristics, which render the resultingmixture suitable for direct-blend process, e.g., good flowcharacteristics.

In certain embodiments, provided herein are methods for preparing acomposition provided herein, comprising: (i) weighing out the desiredamount of Compound A and the desired amount of a first portion ofexcipients; (ii) preparing an aqueous solution of surfactant(s); (iii)passing the mixture of Compound A and the first portion of theexcipients without the surfactant(s) through a screen; (iv) mixing orblending Compound A, the aqueous solution of surfactant(s) and the firstportion of the excipients; (v) drying the mixture; (vi) passing a secondportion of the excipients through a screen; (vii) mixing or blending themixture of step (v) and the second portion of the excipients; (viii)weighing out the desired amount of lubricating agents; (ix) passing thelubricating agents through a screen; (x) mixing or blending the mixtureof step (vii) and the lubricating agents; (xi) compressing the mixtureof step (x); and (ix) coating the compressed mixture with a coatingagent. In one embodiment, the mixture of Compound A, the excipients andthe lubricating agents is compressed into a tablet form. In oneembodiment, the screen is 18 mesh screen. In another embodiment, thescreen is 1000 m screen. In one embodiment, the screen is 20 meshscreen. In another embodiment, the screen is 841 m screen. In oneembodiment, the screen is 30 mesh screen. In another embodiment, thescreen is 595 m screen.

In one such embodiment, Compound A is Compound 1. In another embodiment,Compound A is a pharmaceutically acceptable salt of Compound 1. In yetanother embodiment, Compound A is a solid form of Compound 1.

5.11. Dissolution Profiles

In certain embodiments, the tablets comprising Compound A providedherein have a dissolution profile wherein about A00% of Compound A isreleased in about 10-20 minutes, about 30-40 minutes, about 50-60minutes, about 70-80 minutes, about 90-100 minutes or about 110-120minutes in a 0.1N HCl aqueous solution, a 0.01N HCl aqueous solution oran aqueous buffer solution of about pH 4.5.

In certain embodiments, the tablets comprising Compound A providedherein have a dissolution profile wherein about 50% of Compound A isreleased in about 5-10 minutes in a 0.1N HCl aqueous solution.

In certain embodiments, the tablets comprising Compound A providedherein have a dissolution profile wherein about 50% of Compound A isreleased in about 8 minutes in a 0.1N HCl aqueous solution.

In certain embodiments, the tablets comprising Compound A providedherein have a dissolution profile wherein about 50% of Compound A isreleased in about 1-5 minutes in a 0.01N HCl aqueous solution.

In certain embodiments, the tablets comprising Compound A providedherein have a dissolution profile wherein about 50% of Compound A isreleased in about 3 minutes in a 0.01N HCl aqueous solution.

In certain embodiments, the tablets comprising Compound A providedherein have a dissolution profile wherein about 50% of Compound A isreleased in about 10-15 minutes in an aqueous buffer solutions of aboutpH 4.5.

In certain embodiments, the tablets comprising Compound A providedherein have a dissolution profile wherein about 50% of Compound A isreleased in about 12 minutes in an aqueous buffer solutions of about pH4.5.

In one such embodiment, Compound A is Compound 1. In another embodiment,Compound A is a pharmaceutically acceptable salt of Compound 1. In yetanother embodiment, Compound A is a solid form of Compound 1.

5.12. Salts of Compound 1

Further provided herein are pharmaceutically acceptable salts ofCompound 1, including hydrochloride, sulfate, phosphate, L-tartrate,L-malate, L-lactate, succinate, p-toluenesulfate (tosylate),methanesulfate (mesylate), benzensulfate (besylate), fumarate andcitrate salts.

In certain embodiments, the pharmaceutical compositions and dosage formsof Compound A comprise one or more pharmaceutically acceptable salts ofCompound 1, including hydrochloride, sulfate, phosphate, L-tartrate,L-malate, L-lactate, succinate, p-toluenesulfate (tosylate),methanesulfate (mesylate), benzensulfate (besylate), fumarate andcitrate salts.

In certain embodiments, the methods of use provided herein comprise theadministration of one or more pharmaceutically acceptable salts ofCompound 1, including hydrochloride, sulfate, phosphate, L-tartrate,L-malate, L-lactate, succinate, p-toluenesulfate (tosylate),methanesulfate (mesylate), benzensulfate (besylate), fumarate andcitrate salts.

The salts provided herein (e.g., the HCl salt, H₂SO₄ salt, H₃PO₄ salt,L-tartrate salt, L-lactate salt, L-malate salt, citrate salt, succinatesalt, tosylate salt, mesylate salt, besylate salt and fumarate salt ofCompound 1) may be characterized using a number of methods known to aperson skilled in the art, including, but not limited to, single crystalX-ray diffraction, X-ray powder diffraction (XRPD), microscopy (e.g.,scanning electron microscopy (SEM), polarized light microscopy (PLM) andhot-stage microscopy)), thermal analysis (e.g., differential scanningcalorimetry (DSC)), dynamic vapor sorption (DVS), thermal gravimetricanalysis (TGA), spectroscopy (e.g., infrared, Raman, and solid-statenuclear magnetic resonance), ultra-high performance liquidchromatography (UHPLC), and proton nuclear magnetic resonance (¹H NMR)spectrum. The particle size and size distribution of the salt providedherein may be determined by conventional methods, such as laser lightscattering technique.

It should be understood that the numerical values of the peaks of anX-ray powder diffraction pattern may vary slightly from one machine toanother or from one sample to another, and so the values quoted are notto be construed as absolute, but with an allowable variability, such as+0.2° 2θ (see United State Pharmacopoeia, page 2228 (2003)).

In certain embodiments, provided herein are evaporation methods formaking a salt of Compound 1, comprising 1) dissolving Compound 1 in asolvent to yield a solution; 2) adding an acidic counter-ion; 3)evaporating the solution to yield a solid; and 4) collecting the solid.In certain embodiments, the solvent is ACN, EtOH, EtOAc, Hexane, IPAMeOAc, MTBE, MeNO₂ or acetone. In certain embodiments, the acidiccounter-ion is provided by HCl, H₂SO₄, H₃PO₄, L-tartaric acid, L-lacticacid, L-malic acid, citric acid, succinic acid, p-toluenesulfonic acid,methanesulfonic acid, benzenesulfonic acid or fumaric acid.

5.13. HCl Salt of Compound 1

In one embodiment, provided herein is an HCl salt of Compound 1. Incertain embodiments, the HCl salt has 7 different forms.

In certain embodiments, the HCl salt is prepared by evaporation of asolution comprising Compound 1 and HCl. In certain embodiments, the HClsalt is prepared by evaporation of a solution comprising Compound 1 andHCl in EtOH/IPA, IPA, EtOAc, acetone or water.

In one embodiment, HCl salt form 1 is a hydrate prepared by evaporationof a solution comprising Compound 1 and HCl in ACN, suspension in SGF orexposure to moisture.

In one embodiment, HCl salt form 2 contains water and is prepared byevaporation of a solution comprising Compound 1 and HCl in EtOH/IPA orIPA. In one embodiment, HCl salt form 2 is converted to a hydrate whenexposed to moisture (to HCl salt form 1) or suspended in water (to HClsalt form 7).

In one embodiment, HCl salt form 3 is prepared by evaporation of asolution comprising Compound 1 and HCl in EtOAc.

In one embodiment, HCl salt form 4 is prepared by evaporation of asolution comprising Compound 1 and HCl in acetone.

In one embodiment, HCl salt form 5 is prepared through heating HCl saltform 2 to 180° C. In one embodiment, HCl salt form 5 is converted to ahydrate (HCl salt form 1) when exposed to moisture.

In one embodiment, HCl salt form 6 is a dehydrated hydrate. In oneembodiment, HCl salt form 6 is prepared by heating HCl salt form 2 to220° C. In one embodiment, HCl salt form 6 is converted to a hydrate(HCl salt form 1) when exposed to moisture.

In one embodiment, HCl salt form 7 is a hydrate. In one embodiment, HClsalt form 7 is prepared by suspending HCl salt form 1 in water atambient temperature.

In one embodiment, the HCl salt is a solid. In one embodiment, the HClsalt is crystalline. In one embodiment, the HCl salt is anhydrous. Inone embodiment, the HCl salt is hygroscopic. In another embodiment, theHCl salt is a hydrate. In another embodiment, the HCl salt form 1 is amonohydrate.

In one embodiment, HCl salt form 2 has a TGA thermogram correspondingsubstantially to the representative TGA thermogram as depicted in FIG.34. In certain embodiments, HCl salt form 2 exhibits a TGA thermogramcomprising a total mass loss of approximately 2.82% of the total mass ofthe sample between approximately 25° C. and approximately 119.9° C. whenheated from approximately 25° C. to approximately 300° C. Thus, incertain embodiments, HCl salt form 2 loses about 20.82% of its totalmass when heated from about ambient temperature to about 300° C.

In one embodiment, HCl salt form 2 has a DSC thermogram as depicted inFIG. 34 comprising an endothermic event at 163.0° C. when heated fromapproximately 25° C. to approximately 300° C. In one embodiment, the DSCthermogram further comprises a melt and decomposition event with anonset temperature of about 220° C. when heated from approximately 25° C.to approximately 300° C.

In one embodiment, HCl salt form 2 has a DVS isotherm plot substantiallyas depicted in FIG. 41.

In certain embodiments, solid forms provided herein, e.g., HCl saltforms 1-4, are substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, HCl salt forms 1-4have X-ray powder diffraction patterns substantially as shown in FIG. 6.

In one embodiment, HCl salt forms 1-4 have Raman spectra substantiallyas depicted in FIG. 7.

In certain embodiments, a solid form provided herein, e.g., HCl saltform 1, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, HCl salt form 1 hasan X-ray powder diffraction pattern substantially as shown in FIG. 75.In one embodiment, HCl salt form 1 has one or more characteristic X-raypowder diffraction peaks at approximately 5.5, 7.5, 9.0, 9.7, 11.2,13.1, 13.9, 15.9, 16.5, 17.2, 17.3, 18.3, 19.6, 19.8, 21.7, 22.0, 22.9,23.7, 24.6, 24.9, 25.9, 26.4, 27.3, 27.7, 28.2, 28.5, 29.9, 30.6, 31.0,31.2, 31.7, 32.0, 32.6, 33.0, 33.4, 33.7, 34.2, 36.3, 37.8 or 38.8° 2θas depicted in FIG. 75. In a specific embodiment, HCl salt form 1 hasone, two, three, four, five, six, seven or eight characteristic X-raypowder diffraction peaks at approximately 5.5, 11.2, 17.2, 17.3, 18.3,19.6, 21.7 or 23.7° 2θ. In another embodiment, HCl salt form 1 has one,two, three, four or five characteristic X-ray powder diffraction peaksat approximately 5.5, 13.1, 18.3, 19.6 or 21.7° 2θ. In anotherembodiment, HCl salt form 1 has one, two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen,seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two,twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven,twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three,thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight,thirty-nine or forty characteristic X-ray powder diffraction peaks asset forth in Table 32.

In certain embodiments, a solid form provided herein, e.g., HCl saltform 2, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, HCl salt form 2 hasan X-ray powder diffraction pattern substantially as shown in FIG. 76.In one embodiment, HCl salt form 2 has one or more characteristic X-raypowder diffraction peaks at approximately 5.37, 7.92, 9.23, 9.53, 11.95,12.40, 12.61, 13.09, 14.90, 15.69, 16.52, 17.92, 18.17, 18.64, 18.94,20.54, 20.69, 20.93, 21.36, 21.69, 22.05, 22.80, 23.55, 24.28, 24.71,25.09, 25.25, 25.78, 25.99, 27.02, 28.42, 28.87, 29.63, 30.74, 31.58,31.87, 32.33, 32.76, 33.35, 34.02, 35.10, 36.06, 36.61, 37.00, 37.86,38.10, 39.16 or 39.92° 2θ as depicted in FIG. 76. In a specificembodiment, HCl salt form 2 has one, two, three, four, five, six, sevenor eight characteristic X-ray powder diffraction peaks at approximately7.92, 9.23, 18.64, 18.94, 20.69, 25.25, 27.02 or 29.63° 2θ. In anotherembodiment, HCl salt form 2 has one, two, three, four or fivecharacteristic X-ray powder diffraction peaks at approximately 7.92,9.23, 18.94, 20.69 or 29.63° 2θ. In another embodiment, HCl salt form 2has one, two, three, four or five characteristic X-ray powderdiffraction peaks at approximately 7.92, 9.23, 11.95, 12.40 or 18.94°2θ. In another embodiment, HCl salt form 2 has one, two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one,twenty-two, twenty-three, twenty-four, twenty-five, twenty-six,twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two,thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven,thirty-eight, thirty-nine, forty, forty-one, forty-two, forty-three,forty-four, forty-five, forty-six, forty-seven or forty-eightcharacteristic X-ray powder diffraction peaks as set forth in Table 33.

In certain embodiments, a solid form provided herein, e.g., HCl saltform 3, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, HCl salt form 3 hasan X-ray powder diffraction pattern substantially as shown in FIG. 77.In one embodiment, HCl salt form 3 has one or more characteristic X-raypowder diffraction peaks at approximately 5.71, 9.48, 9.85, 11.34,13.24, 14.10, 16.75, 17.86, 18.44, 19.67, 21.82, 23.10, 23.84, 25.03,26.04, 27.81, 30.65, 31.83 or 38.91° 2θ as depicted in FIG. 77. In aspecific embodiment, HCl salt form 3 has one, two, three, four, five,six, seven or eight characteristic X-ray powder diffraction peaks atapproximately 5.71, 9.85, 11.34, 13.24, 16.75, 18.44, 19.67 or 21.82°2θ. In another embodiment, HCl salt form 3 has one, two, three, four orfive characteristic X-ray powder diffraction peaks at approximately5.71, 11.34, 13.24, 16.75 or 18.44° 2θ. In another embodiment, HCl saltform 3 has one, two, three, four or five characteristic X-ray powderdiffraction peaks at approximately 5.71, 9.48, 11.34, 13.24 or 18.44°2θ. In another embodiment, HCl salt form 3 has one, two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,fifteen, sixteen, seventeen, eighteen or nineteen characteristic X-raypowder diffraction peaks as set forth in Table 34.

In certain embodiments, a solid form provided herein, e.g., HCl saltform 4, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, HCl salt form 4 hasan X-ray powder diffraction pattern substantially as shown in FIG. 78.In one embodiment, HCl salt form 4 has one or more characteristic X-raypowder diffraction peaks at approximately 5.65, 5.73, 7.50, 9.31, 9.77,11.38, 13.77, 14.23, 16.20, 17.16, 17.54, 18.16, 18.69, 19.06, 20.56,21.65, 21.75, 22.10, 22.65, 23.05, 24.04, 26.18, 28.30, 28.45, 28.70,29.59, 30.90, 32.47 or 35.63° 2θ as depicted in FIG. 78. In a specificembodiment, HCl salt form 4 has one, two, three, four, five, six, sevenor eight characteristic X-ray powder diffraction peaks at approximately5.65, 5.73, 9.77, 11.38, 13.77, 17.16, 21.65 or 29.59° 2θ. In anotherembodiment, HCl salt form 4 has one, two, three, four or fivecharacteristic X-ray powder diffraction peaks at approximately 5.65,5.73, 9.77, 11.38 or 13.77° 2θ. In another embodiment, HCl salt form 4has one, two, three, four or five characteristic X-ray powderdiffraction peaks at approximately 5.65, 9.77, 11.38, 13.77 or 21.65°2θ. In another embodiment, HCl salt form 4 has one, two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one,twenty-two, twenty-three, twenty-four, twenty-five, twenty-six,twenty-seven, twenty-eight or twenty-nine characteristic X-ray powderdiffraction peaks as set forth in Table 35.

In certain embodiments, a solid form provided herein, e.g., HCl saltform 5, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, HCl salt form 5 hasan X-ray powder diffraction pattern substantially as shown in FIG. 79.In one embodiment, HCl salt form 5 has one or more characteristic X-raypowder diffraction peaks at approximately 5.63, 6.29, 7.61, 8.45, 9.74,10.76, 11.27, 12.23, 12.59, 13.16, 14.02, 14.63, 15.97, 16.63, 16.92,17.35, 17.74, 18.40, 18.69, 19.10, 19.66, 21.80, 22.63, 23.05, 23.80,24.58, 24.98, 25.94, 26.51, 27.78, 28.25, 28.57, 30.62, 31.38, 31.78,32.61, 33.01, 33.40, 35.40, 37.88 or 38.82° 2θ as depicted in FIG. 79.In a specific embodiment, HCl salt form 5 has one, two, three, four,five, six, seven or eight characteristic X-ray powder diffraction peaksat approximately 5.63, 17.35, 18.40, 18.69, 19.66, 21.80, 23.80 or25.94° 2θ. In another embodiment, HCl salt form 5 has one, two, three,four or five characteristic X-ray powder diffraction peaks atapproximately 5.63, 18.69, 19.66, 21.80 or 23.80° 2θ. In anotherembodiment, HCl salt form 5 has one, two, three, four or fivecharacteristic X-ray powder diffraction peaks at approximately 5.63,8.45, 10.76, 14.63 or 21.80° 2θ. In another embodiment, HCl salt form 5has one, two, three, four, five, six, seven, eight, nine, ten, eleven,twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen,nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four,twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine,thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five,thirty-six, thirty-seven, thirty-eight, thirty-nine, forty or forty-onecharacteristic X-ray powder diffraction peaks as set forth in Table 36.

In certain embodiments, a solid form provided herein, e.g., HCl saltform 6, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, HCl salt form 6 hasan X-ray powder diffraction pattern substantially as shown in FIG. 80.In one embodiment, HCl salt form 6 has one or more characteristic X-raypowder diffraction peaks at approximately 5.58, 7.61, 8.27, 9.13, 9.74,11.19, 13.14, 13.99, 15.91, 16.65, 16.87, 17.33, 18.38, 19.67, 19.92,21.79, 21.99, 23.03, 23.32, 23.77, 24.66, 24.97, 25.33, 25.92, 26.52,27.38, 27.76, 28.24, 28.54, 30.62, 31.34, 31.74, 32.63, 33.04, 33.47,36.38, 37.83 or 38.79° 2θ as depicted in FIG. 80. In a specificembodiment, HCl salt form 6 has one, two, three, four, five, six, sevenor eight characteristic X-ray powder diffraction peaks at approximately5.58, 11.19, 13.14, 17.33, 18.38, 19.67, 21.79 or 23.77° 2θ. In anotherembodiment, HCl salt form 6 has one, two, three, four or fivecharacteristic X-ray powder diffraction peaks at approximately 5.58,17.33, 18.38, 19.67 or 21.79° 2θ. In another embodiment, HCl salt form 6has one, two, three, four or five characteristic X-ray powderdiffraction peaks at approximately 5.58, 8.27, 18.38, 19.67 or 21.79°2θ. In another embodiment, HCl salt form 6 has one, two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one,twenty-two, twenty-three, twenty-four, twenty-five, twenty-six,twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two,thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven orthirty-eight characteristic X-ray powder diffraction peaks as set forthin Table 37.

In certain embodiments, a solid form provided herein, e.g., HCl saltform 7, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, HCl salt form 7 hasan X-ray powder diffraction pattern substantially as shown in FIG. 81.In one embodiment, HCl salt form 7 has one or more characteristic X-raypowder diffraction peaks at approximately 5.54, 7.61, 8.95, 9.85, 11.14,12.86, 14.14, 15.77, 16.83, 17.29, 17.51, 18.04, 18.33, 18.69, 19.82,21.94, 23.05, 23.90, 28.28, 30.66, 32.02 or 38.98° 2θ as depicted inFIG. 81. In a specific embodiment, HCl salt form 7 has one, two, three,four, five, six, seven or eight characteristic X-ray powder diffractionpeaks at approximately 5.54, 7.61, 11.14, 18.04, 19.82, 21.94, 23.05 or38.98° 2θ. In another embodiment, HCl salt form 7 has one, two, three,four or five characteristic X-ray powder diffraction peaks atapproximately 5.54, 7.61, 18.04, 19.82 or 23.05° 2θ. In anotherembodiment, HCl salt form 7 has one, two, three, four or fivecharacteristic X-ray powder diffraction peaks at approximately 5.54,7.61, 8.95, 12.86 or 18.04° 2θ. In another embodiment, HCl salt form 7has one, two, three, four, five, six, seven, eight, nine, ten, eleven,twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen,nineteen, twenty, twenty-one or twenty-two characteristic X-ray powderdiffraction peaks as set forth in Table 38.

5.14. H₂SO₄ Salt of Compound 1

In one embodiment, provided herein is an H₂SO₄ salt of Compound 1. Incertain embodiments, the H₂SO₄ salt has 3 different forms.

In one embodiment, H₂SO₄ salt form 1 is prepared by evaporation of asolution comprising Compound 1 and H₂SO₄ in ACN, IPA or EtOAc.

In one embodiment, H₂SO₄ salt form 2 is prepared by evaporation of asolution comprising Compound 1 and H₂SO₄ in acetone.

In one embodiment, H₂SO₄ salt form 3 is prepared by storing form 1 at80° C. and 75% relative humidity. In one embodiment, H₂SO₄ salt form 3is prepared by storing form 1 at 80° C. and 75% relative humidity for 2weeks.

In one embodiment, the H₂SO₄ salt is a solid. In one embodiment, theH₂SO₄ salt is crystalline. In one embodiment, the H₂SO₄ salt isanhydrous. In one embodiment, the H₂SO₄ salt is hygroscopic. In anotherembodiment, the H₂SO₄ salt is a hydrate.

In certain embodiments, the H₂SO₄ salt is prepared by evaporation. Inone embodiment, the H₂SO₄ salt is prepared by evaporation of a solutioncomprising Compound 1 and H₂SO₄ in ACN, IPA, EtOAc or acetone.

In one embodiment, H₂SO₄ salt form 1 has a TGA thermogram correspondingsubstantially to the representative TGA thermogram as depicted in FIG.35. In certain embodiments, H₂SO₄ form 1 salt exhibits a TGA thermogramcomprising a total mass loss of approximately 0.28% of the total mass ofthe sample between approximately 25° C. and approximately 119.9° C. whenheated from approximately 25° C. to approximately 300° C. Thus, incertain embodiments, H₂SO₄ salt form 1 loses about 0.28% of its totalmass when heated from about ambient temperature to about 300° C.

In one embodiment, H₂SO₄ salt form 1 has a DSC thermogram as depicted inFIG. 35 comprising an T_(g)-like event between about 86.0° C. and 88.4°C. when heated from approximately 25° C. to approximately 300° C. In oneembodiment, the DSC thermogram further comprises a melting anddecomposition event with an onset temperature of about 235° C. whenheated from approximately 25° C. to approximately 300° C.

In one embodiment, H₂SO₄ salt form 1 has a DVS isotherm plotsubstantially as depicted in FIG. 43.

In certain embodiments, solid forms provided herein, e.g., H₂SO₄ saltforms 1-3, are substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, H₂SO₄ salt forms 1-2have X-ray powder diffraction patterns substantially as shown in FIG. 8.In another embodiment, the H₂SO₄ salt form 3 has an X-ray powderdiffraction pattern substantially as shown in FIG. 84.

In one embodiment, H₂SO₄ salt forms 1-2 have Raman spectra substantiallyas depicted in FIG. 9.

In certain embodiments, a solid form provided herein, e.g., H₂SO₄ saltform 1, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, H₂SO₄ salt form 1has an X-ray powder diffraction pattern substantially as shown in FIG.82. In one embodiment, H₂SO₄ salt form 1 has one or more characteristicX-ray powder diffraction peaks at approximately 5.40, 5.66, 9.02, 10.74,14.78, 16.16, 16.65, 17.65, 18.18, 18.69, 19.67, 20.50, 21.62, 22.28,22.75, 24.13, 24.57, 24.88, 25.42, 26.55, 28.49, 29.17, 29.88, 31.29,32.15, 32.66, 33.21, 34.02, 35.78, 36.86, 37.43, 38.27 or 39.64° 2θ asdepicted in FIG. 82. In a specific embodiment, H₂SO₄ salt form 1 hasone, two, three, four, five, six, seven or eight characteristic X-raypowder diffraction peaks at approximately 5.40, 10.74, 18.18, 18.69,21.62, 22.28, 22.75 or 26.55° 2θ. In another embodiment, H₂SO₄ salt form1 has one, two, three, four or five characteristic X-ray powderdiffraction peaks at approximately 5.40, 18.18, 18.69, 21.62 or 22.28°2θ. In another embodiment, H₂SO₄ salt form 1 has one, two, three, fouror five characteristic X-ray powder diffraction peaks at approximately5.40, 10.74, 18.18, 18.69 or 22.28° 2θ. In another embodiment, H₂SO₄salt form 1 has one, two, three, four, five, six, seven, eight, nine,ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen,eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three,twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight,twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four,thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine orforty characteristic X-ray powder diffraction peaks as set forth inTable 39.

In certain embodiments, a solid form provided herein, e.g., H₂SO₄ saltform 2, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, H₂SO₄ salt form 2has an X-ray powder diffraction pattern substantially as shown in FIG.83. In one embodiment, H₂SO₄ salt form 2 has one or more characteristicX-ray powder diffraction peaks at approximately 5.63, 5.67, 15.25,16.08, 17.87, 18.57, 21.83, 22.24, 22.75, 25.90, 26.53 or 27.18° 2θ asdepicted in FIG. 83. In a specific embodiment, H₂SO₄ salt form 2 hasone, two, three, four, five, six, seven or eight characteristic X-raypowder diffraction peaks at approximately 5.63, 5.67, 15.25, 16.08,17.87, 18.57, 22.24 or 22.75° 2θ. In another embodiment, H₂SO₄ salt form2 has one, two, three, four or five characteristic X-ray powderdiffraction peaks at approximately 5.63, 5.67, 17.87, 18.57 or 22.75°2θ. In another embodiment, H₂SO₄ salt form 2 has one, two, three, fouror five characteristic X-ray powder diffraction peaks at approximately5.63, 11.30, 15.25, 17.87 or 18.57° 2θ. In another embodiment, H₂SO₄salt form 2 has one, two, three, four, five, six, seven, eight, nine,ten, eleven or twelve characteristic X-ray powder diffraction peaks asset forth in Table 40.

In certain embodiments, a solid form provided herein, e.g., H₂SO₄ saltform 3, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, H₂SO₄ salt form 3has an X-ray powder diffraction pattern substantially as shown in FIG.84. In one embodiment, H₂SO₄ salt form 3 has one or more characteristicX-ray powder diffraction peaks at approximately 5.60, 10.68, 11.22,12.41, 13.81, 15.11, 15.96, 16.86, 17.67, 18.10, 18.48, 18.78, 19.15,21.53, 22.10, 22.38, 22.61, 23.65, 24.56, 25.22, 25.85, 26.27, 27.24,33.38, 34.20 or 37.96° 2θ as depicted in FIG. 84. In a specificembodiment, H₂SO₄ salt form 3 has one, two, three, four, five, six,seven or eight characteristic X-ray powder diffraction peaks atapproximately 5.60, 17.67, 11.22, 22.38, 15.11, 18.10, 22.61, 22.10,27.24, 10.68, 18.48, or 15.96° 2θ. In another embodiment, H₂SO₄ saltform 3 has one, two, three, four or five characteristic X-ray powderdiffraction peaks at approximately 5.60, 17.67, 11.22, 22.38, or 15.11°2θ. In another embodiment, H₂SO₄ salt form 2 has one, two, three, fouror five characteristic X-ray powder diffraction peaks at approximately5.60, 11.22, 15.11, 15.96, 17.67 or 19.15° 2θ. In another embodiment,H₂SO₄ salt form 3 has one, two, three, four, five, six, seven, eight,nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen,seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two,twenty-three, twenty-four, twenty-five or twenty-six characteristicX-ray powder diffraction peaks as set forth in Table 41.

5.15. H₃PO₄ Salt of Compound 1

In one embodiment, provided herein is an H₃PO₄ salt.

In one embodiment, the H₃PO₄ salt is a solid. In one embodiment, theH₃PO₄ salt is crystalline. In one embodiment, the H₃PO₄ salt isanhydrous. In one embodiment, the H₃PO₄ salt is not hygroscopic.

In certain embodiments, the H₃PO₄ salt provided herein is prepared byevaporation of a solution comprising Compound 1 and H₃PO₄. In oneembodiment, the H₃PO₄ salt is prepared by evaporation of a solutioncomprising Compound 1 and H₃PO₄ in ACN, IPA, EtOAc or acetone.

In one embodiment, the H₃PO₄ salt has a TGA thermogram correspondingsubstantially to the representative TGA thermogram as depicted in FIG.36. In certain embodiments, the H₃PO₄ salt exhibits a TGA thermogramcomprising a total mass loss of approximately 0.25% of the total mass ofthe sample between approximately 25° C. and approximately 119.9° C. whenheated from approximately 25° C. to approximately 300° C. Thus, incertain embodiments, the H₃PO₄ salt loses about 0.25% of its total masswhen heated from about ambient temperature to about 300° C.

In one embodiment, the H₃PO₄ salt has a DSC thermogram as depicted inFIG. 36 comprising a dehydration event with an onset temperature ofabout 169.9° C. when heated from approximately 25° C. to approximately300° C. In one embodiment, the DSC thermogram further comprises amelting and decomposition event with an onset temperature of about238.3° C. when heated from approximately 25° C. to approximately 300° C.

In one embodiment, the H₃PO₄ salt has a DVS isotherm plot substantiallyas depicted in FIG. 45.

In certain embodiments, a solid form provided herein, e.g., a H₃PO₄salt, is substantially crystalline, as indicated by, e.g., X-ray powderdiffraction measurements. In one embodiment, the H₃PO₄ salt has an X-raypowder diffraction pattern substantially as shown in FIG. 10.

In one embodiment, the H₃PO₄ salt has a Raman spectrum substantially asdepicted in FIG. 11.

In certain embodiments, a solid form provided herein, e.g., H₃PO₄ salt,is substantially crystalline, as indicated by, e.g., X-ray powderdiffraction measurements. In one embodiment, H₃PO₄ salt has an X-raypowder diffraction pattern substantially as shown in FIG. 85. In oneembodiment, H₃PO₄ salt has one or more characteristic X-ray powderdiffraction peaks at approximately 5.58, 5.73, 11.30, 15.27, 16.07,16.37, 16.95, 17.46, 17.72, 18.37, 20.64, 20.98, 21.73, 22.34, 22.66,23.31, 23.65, 24.14, 25.88, 26.42, 28.10, 28.39, 29.89, 30.38, 30.88,31.35, 33.13, 34.32, 35.08, 35.91, 37.43 or 38.89° 2θ as depicted inFIG. 85. In a specific embodiment, H₃PO₄ salt has one, two, three, four,five, six, seven or eight characteristic X-ray powder diffraction peaksat approximately 5.58, 5.73, 11.30, 15.27, 16.95, 23.65, 25.88 or 28.39°2θ. In another embodiment, H₃PO₄ salt has one, two, three, four or fivecharacteristic X-ray powder diffraction peaks at approximately 5.58,5.73, 11.30, 15.27 or 28.39° 2θ. In another embodiment, H₃PO₄ salt hasone, two, three, four, five, six, seven, eight, nine, ten, eleven,twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen,nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four,twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine,thirty, thirty-one or thirty-two characteristic X-ray powder diffractionpeaks as set forth in Table 50.

5.16. L-Tartrate Salt of Compound 1

In one embodiment, provided herein is an L-tartrate salt of Compound 1.

In one embodiment, the L-tartrate salt is a solid. In one embodiment,the L-tartrate salt is crystalline. In one embodiment, the L-tartratesalt is slightly hygroscopic. In another embodiment, the L-tartrate saltis a hydrate. In another embodiment, the L-tartrate salt is a dihydrate.In another embodiment, the L-tartrate salt is a hemi-tartrate dihydrate.

In certain embodiments, the L-tartrate salt is prepared by evaporationof a solution comprising Compound 1 and L-tartaric acid. In oneembodiment, the L-tartrate salt is prepared by evaporation of a solutioncomprising Compound 1 and L-tartaric acid in ACN, IPA, EtOAc or acetone.

In one embodiment, the stoichiometric ratio for Compound 1 to L-tartaricacid is about 2:1 in the L-tartrate salt.

In one embodiment, the L-tartrate salt has a TGA thermogramcorresponding substantially to the representative TGA thermogram asdepicted in FIG. 37. In certain embodiments, the L-tartrate saltexhibits a TGA thermogram comprising a total mass loss of approximately3.97% of the total mass of the sample between approximately 25° C. andapproximately 119.9° C. when heated from approximately 25° C. toapproximately 300° C. Thus, in certain embodiments, the L-tartrate saltloses about 3.97% of its total mass when heated from about ambienttemperature to about 300° C.

In one embodiment, the L-tartrate salt has a DSC thermogram as depictedin FIG. 37 comprising a dehydration event with an onset temperature ofabout 89.5° C. when heated from approximately 25° C. to approximately300° C. In one embodiment, the DSC thermogram further comprises a meltand decomposition event with an onset temperature of about 201.5° C.when heated from approximately 25° C. to approximately 300° C.

In one embodiment, the L-tartrate salt has a DVS isotherm plotsubstantially as depicted in FIG. 47.

In certain embodiments, a solid form provided herein, e.g., a L-tartratesalt, is substantially crystalline, as indicated by, e.g., X-ray powderdiffraction measurements. In one embodiment, the L-tartrate salt has anX-ray powder diffraction pattern substantially as shown in FIG. 12.

In one embodiment, the L-tartrate salt has a Raman spectrumsubstantially as depicted in FIG. 13.

In certain embodiments, a solid form provided herein, e.g., L-tartratesalt form 1, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, L-tartrate salt form1 has an X-ray powder diffraction pattern substantially as shown in FIG.88. In one embodiment, L-tartrate salt form 1 has one or morecharacteristic X-ray powder diffraction peaks at approximately 6.04,9.47, 12.14, 13.73, 14.57, 15.19, 16.19, 16.68, 17.30, 18.27, 19.98,20.31, 21.14, 22.08, 22.75, 23.21, 23.84, 24.33, 25.92, 26.51, 27.09,27.75, 28.44, 29.52, 31.15, 31.83, 32.73, 33.31, 34.99, 35.55, 36.80,37.25, 37.77 or 38.41° 2θ as depicted in FIG. 88. In a specificembodiment, L-tartrate salt form 1 has one, two, three, four, five, six,seven or eight characteristic X-ray powder diffraction peaks atapproximately 6.04, 16.19, 16.68, 17.30, 19.98, 20.31, 23.21 or 24.33°2θ. In another embodiment, L-tartrate salt form 1 has one, two, three,four or five characteristic X-ray powder diffraction peaks atapproximately 6.04, 16.19, 16.68, 19.98 or 24.33° 2θ. In anotherembodiment, L-tartrate salt form 1 has one, two, three, four or fivecharacteristic X-ray powder diffraction peaks at approximately 6.04,12.14, 16.19, 18.27 or 24.33° 2θ. In another embodiment, L-tartrate saltform 1 has one, two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen,eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three,twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight,twenty-nine, thirty, thirty-one, thirty-two, thirty-three or thirty-fourcharacteristic X-ray powder diffraction peaks as set forth in Table 51.

In certain embodiments, a solid form provided herein, e.g., L-tartratesalt form 2, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, L-tartrate salt form2 has an X-ray powder diffraction pattern substantially as shown in FIG.89. In one embodiment, L-tartrate salt form 2 has one or morecharacteristic X-ray powder diffraction peaks at approximately 5.02,6.29, 6.46, 9.71, 12.47, 12.63, 15.21, 16.51, 16.56, 17.23, 18.82,20.72, 22.49, 22.71, 24.04, 24.86, 24.95, 27.08, 28.25, 29.30, 30.78,31.16, 31.30, 33.13, 33.96, 34.36, 34.87, 35.03, 35.14, 35.29, 36.36 or36.58° 2θ as depicted in FIG. 89. In a specific embodiment, L-tartratesalt form 2 has one, two, three, four, five, six, seven or eightcharacteristic X-ray powder diffraction peaks at approximately 6.29,6.46, 12.63, 16.51, 17.23, 20.72, 24.04 or 24.95° 2θ. In anotherembodiment, L-tartrate salt form 2 has one, two, three, four or fivecharacteristic X-ray powder diffraction peaks at approximately 6.29,6.46, 16.51, 20.72 or 24.04° 2θ. In another embodiment, L-tartrate saltform 2 has one, two, three, four or five characteristic X-ray powderdiffraction peaks at approximately 6.29, 12.63, 16.51, 18.82 or 24.95°2θ. In another embodiment, L-tartrate salt form 2 has one, two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty,twenty-one, twenty-two, twenty-three, twenty-four, twenty-five,twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-oneor thirty-two characteristic X-ray powder diffraction peaks as set forthin Table 52.

5.17. L-Lactate Salt of Compound 1

In one embodiment, provided herein is an L-lactate salt of Compound 1.In certain embodiments, the L-lactate salt has 2 different forms.

In certain embodiments, the L-lactate salt is prepared by evaporation ofa solution comprising Compound 1 and L-lactic acid. In one embodiment,the L-lactate salt is prepared by evaporation of a solution comprisingCompound 1 and L-lactic acid in hexane or EtOAc.

In one embodiment, L-lactate salt form 1 is prepared by evaporation of asolution comprising Compound 1 and L-lactic acid in hexane. In oneembodiment, L-lactate salt form 2 is prepared by evaporation of asolution comprising Compound 1 and L-lactic acid in EtOAc.

In one embodiment, the L-lactate salt is a solid. In one embodiment, theL-lactate salt is crystalline. In one embodiment, the L-lactate salt ismoderately hygroscopic. In another embodiment, the L-lactate salt is ahydrate.

In one embodiment, L-lactate salt form 2 has a TGA thermogramcorresponding substantially to the representative TGA thermogram asdepicted in FIG. 39. In certain embodiments, L-lactate salt form 1exhibits a TGA thermogram comprising a total mass loss of approximately1.74% of the total mass of the sample between approximately 25° C. andapproximately 119.9° C. when heated from approximately 25° C. toapproximately 300° C. Thus, in certain embodiments, L-lactate salt form1 loses about 1.74% of its total mass when heated from about ambienttemperature to about 300° C.

In one embodiment, L-tartrate salt form 2 has a DSC thermogram asdepicted in FIG. 39 comprising a dehydration event with an onsettemperature of about 76.5° C. when heated from approximately 25° C. toapproximately 300° C. In one embodiment, the DSC thermogram furthercomprises a melt and decomposition event with an onset temperature ofabout 145.3° C. when heated from approximately 25° C. to approximately300° C.

In one embodiment, L-lactate salt form 2 has a DVS isotherm plotsubstantially as depicted in FIG. 52.

In certain embodiments, solid forms provided herein, e.g., L-lactatesalt forms 1-2, are substantially crystalline, as indicated by, e.g.,X-ray powder diffraction measurements. In one embodiment, L-lactate saltforms 1-2 have X-ray powder diffraction patterns substantially as shownin FIG. 16.

In one embodiment, L-lactate salt forms 1-2 have Raman spectrasubstantially as depicted in FIG. 17.

In certain embodiments, a solid form provided herein, e.g., L-lactatesalt form 1, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, L-lactate salt form1 has an X-ray powder diffraction pattern substantially as shown in FIG.86. In one embodiment, L-lactate salt form 1 has one or morecharacteristic X-ray powder diffraction peaks at approximately 5.77,7.93, 9.57, 9.81, 10.01, 11.69, 12.09, 12.81, 13.72, 14.39, 14.66,16.10, 16.89, 17.19, 17.70, 18.89, 19.20, 19.54, 19.72, 20.16, 20.43,20.96, 21.55, 21.84, 23.12, 24.22, 24.67, 24.92, 25.21, 26.19, 27.06,28.55, 29.20, 30.43, 32.82, 34.36 or 36.29° 2θ as depicted in FIG. 86.In a specific embodiment, L-lactate salt form 1 has one, two, three,four, five, six, seven or eight characteristic X-ray powder diffractionpeaks at approximately 5.77, 9.57, 9.81, 16.10, 18.89, 19.54, 20.16 or24.22° 2θ. In another embodiment, L-lactate salt form 1 has one, two,three, four or five characteristic X-ray powder diffraction peaks atapproximately 5.77, 9.57, 16.10, 19.54 or 20.16° 2θ. In anotherembodiment, L-lactate salt form 1 has one, two, three, four or fivecharacteristic X-ray powder diffraction peaks at approximately 5.77,7.93, 16.10, 20.16 or 24.22° 2θ. In another embodiment, L-lactate saltform 1 has one, two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen,eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three,twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight,twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four,thirty-five, thirty-six or thirty-seven characteristic X-ray powderdiffraction peaks as set forth in Table 53.

In certain embodiments, a solid form provided herein, e.g., L-lactatesalt form 2, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, L-lactate salt form2 has an X-ray powder diffraction pattern substantially as shown in FIG.87. In one embodiment, L-lactate salt form 2 has one or morecharacteristic X-ray powder diffraction peaks at approximately 9.69,10.23, 12.14, 12.74, 13.29, 13.51, 15.62, 16.05, 16.29, 16.87, 17.02,17.55, 18.00, 18.51, 18.97, 19.47, 20.41, 20.98, 21.45, 22.39, 22.64,23.08, 23.50, 23.84, 24.03, 24.46, 24.88, 25.21, 26.42, 26.86, 27.24,27.77, 28.23, 28.53, 30.47, 31.04, 31.58, 32.44, 33.93, 35.53, 36.58,37.11 or 38.68° 2θ as depicted in FIG. 87. In a specific embodiment,L-lactate salt form 2 has one, two, three, four, five, six, seven oreight characteristic X-ray powder diffraction peaks at approximately9.69, 10.23, 13.29, 17.02, 18.51, 18.97, 19.47 or 20.41° 2θ. In anotherembodiment, L-lactate salt form 2 has one, two, three, four or fivecharacteristic X-ray powder diffraction peaks at approximately 10.23,17.02, 18.97, 19.47 or 20.41° 2θ. In another embodiment, L-lactate saltform 2 has one, two, three, four or five characteristic X-ray powderdiffraction peaks at approximately 9.69, 10.23, 13.29, 17.02 or 18.97°2θ. In another embodiment, L-lactate salt form 2 has one, two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty,twenty-one, twenty-two, twenty-three, twenty-four, twenty-five,twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one,thirty-two, thirty-three, thirty-four, thirty-five, thirty-six,thirty-seven, thirty-eight, thirty-nine, forty, forty-one, forty-two orforty-three characteristic X-ray powder diffraction peaks as set forthin Table 54.

5.18. L-Malate Salt of Compound 1

In one embodiment, provided herein is an L-malate salt of Compound 1. Incertain embodiments, the L-malate salt has 4 different forms.

In one embodiment, the L-malate salt is a solid. In one embodiment, theL-malate salt is crystalline. In one embodiment, the L-malate salt ishygroscopic. In another embodiment, the L-malate salt is a hydrate.

In certain embodiments, the L-malate salt is prepared by evaporation ofa solution comprising Compound 1 and L-malic acid. In one embodiment,the L-malate salt is prepared by evaporation of a solution comprisingCompound 1 and L-malic acid in ACN, IPA, EtOAc or acetone.

In one embodiment, L-malate salt form 1 is prepared by evaporation of asolution comprising Compound 1 and L-malic acid in ACN.

In one embodiment, L-malate salt form 2 is prepared by evaporation of asolution comprising Compound 1 and L-malic acid in MeNO₂.

In one embodiment, L-malate salt form 3 is prepared by evaporation of asolution comprising Compound 1 and L-malic acid in EtOAc.

In one embodiment, L-malate salt form 4 is prepared by evaporation of asolution comprising Compound 1 and L-malic acid in IPA.

In one embodiment, the stoichiometric ratio for Compound 1 to L-malicacid is about 1:1 in the L-malic salt.

In one embodiment, the L-malate salt form 2 has a TGA thermogramcorresponding substantially to the representative TGA thermogram asdepicted in FIG. 38. In certain embodiments, the L-malate salt exhibitsa TGA thermogram comprising a total mass loss of approximately 1.21% ofthe total mass of the sample between approximately 25° C. andapproximately 94.8° C. when heated from approximately 25° C. toapproximately 300° C. Thus, in certain embodiments, the L-malate saltloses about 1.21% of its total mass when heated from about ambienttemperature to about 300° C.

In one embodiment, the L-malate salt form 2 has a DSC thermogram asdepicted in FIG. 38 comprising a dehydration event with an onsettemperature of about 94.8° C. when heated from approximately 25° C. toapproximately 300° C. In one embodiment, the DSC thermogram furthercomprises a solid-solid transition event with an onset temperature ofabout 100.8° C. when heated from approximately 25° C. to approximately300° C.

In one embodiment, the L-malate salt form 2 has a DVS isotherm plotsubstantially as depicted in FIG. 50.

In certain embodiments, solid forms provided herein, e.g., L-malate saltforms 1-4, are substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, L-malate salt forms1-4 have an X-ray powder diffraction pattern substantially as shown inFIG. 18.

In one embodiment, L-malate forms 1-4 salt have Raman spectrasubstantially as depicted in FIG. 19.

In certain embodiments, a solid form provided herein, e.g., L-malatesalt form 1, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, L-malate salt form 1has an X-ray powder diffraction pattern substantially as shown in FIG.90. In one embodiment, L-malate salt form 1 has one or morecharacteristic X-ray powder diffraction peaks at approximately 5.52,11.12, 15.86 or 17.18° 2θ as depicted in FIG. 90. In another embodiment,L-malate salt form 1 has one, two, three or four characteristic X-raypowder diffraction peaks at approximately 5.52, 11.12, 15.86 or 17.18°2θ. In another embodiment, L-malate salt form 1 has one, two, three orfour characteristic X-ray powder diffraction peaks as set forth in Table55.

In certain embodiments, a solid form provided herein, e.g., L-malatesalt form 2, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, L-malate salt form 2has an X-ray powder diffraction pattern substantially as shown in FIG.91. In one embodiment, L-malate salt form 2 has one or morecharacteristic X-ray powder diffraction peaks at approximately 5.48,6.15, 7.56, 8.50, 8.99, 9.50, 11.08, 12.21, 12.97, 15.23, 16.09, 17.16,17.50, 18.01, 18.48, 19.21, 19.69, 20.38, 21.09, 21.75, 22.47, 22.72,23.70, 24.44, 24.96, 25.23, 25.80, 26.20, 26.51, 27.78, 28.41, 30.01,30.41, 32.95, 34.90, 35.28, 35.91, 36.41 or 37.63° 2θ as depicted inFIG. 91. In a specific embodiment, L-malate salt form 2 has one, two,three, four, five, six, seven or eight characteristic X-ray powderdiffraction peaks at approximately 5.48, 6.15, 7.56, 12.97, 15.23,17.16, 18.48 or 21.09° 2θ. In another embodiment, L-malate salt form 2has one, two, three, four or five characteristic X-ray powderdiffraction peaks at approximately 5.48, 6.15, 7.56, 18.48 or 21.09° 2θ.In another embodiment, L-malate salt form 2 has one, two, three, four orfive characteristic X-ray powder diffraction peaks at approximately5.48, 6.15, 7.56, 15.23 or 21.09° 2θ. In another embodiment, L-malatesalt form 2 has one, two, three, four, five, six, seven, eight, nine,ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen,eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three,twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight,twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four,thirty-five, thirty-six, thirty-seven, thirty-eight or thirty-ninecharacteristic X-ray powder diffraction peaks as set forth in Table 56.

In certain embodiments, a solid form provided herein, e.g., L-malatesalt form 3, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, L-malate salt form 3has an X-ray powder diffraction pattern substantially as shown in FIG.92. In one embodiment, L-malate salt form 3 has one or morecharacteristic X-ray powder diffraction peaks at approximately 4.89,5.49, 7.25, 11.74, 12.39, 15.76, 16.34, 16.73, 19.79, 20.54 or 21.23° 2θas depicted in FIG. 92. In a specific embodiment, L-malate salt form 3has one, two, three, four, five, six, seven or eight characteristicX-ray powder diffraction peaks at approximately 4.89, 5.49, 7.25, 11.74,12.39, 15.76, 16.73 or 20.54° 2θ. In another embodiment, L-malate saltform 3 has one, two, three, four or five characteristic X-ray powderdiffraction peaks at approximately 4.89, 5.49, 7.25, 15.76 or 20.54° 2θ.In another embodiment, L-malate salt form 3 has one, two, three, four orfive characteristic X-ray powder diffraction peaks at approximately4.89, 5.49, 7.25, 11.74 or 15.76° 2θ. In another embodiment, L-malatesalt form 3 has one, two, three, four, five, six, seven, eight, nine,ten or eleven characteristic X-ray powder diffraction peaks as set forthin Table 57.

In certain embodiments, a solid form provided herein, e.g., L-malatesalt form 4, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, L-malate salt form 4has an X-ray powder diffraction pattern substantially as shown in FIG.93. In one embodiment, L-malate salt form 4 has one or morecharacteristic X-ray powder diffraction peaks at approximately 5.91,8.34, 10.45, 10.91, 12.67, 13.10, 13.48, 15.34, 16.71, 17.49, 17.89,18.22, 18.72, 18.95, 19.41, 19.84, 20.21, 20.77, 21.22, 21.62, 21.91,22.60, 23.99, 24.56, 25.03, 26.20, 27.19, 27.52, 28.45, 29.19, 29.60,29.96, 30.24, 30.99, 31.61, 34.44, 35.66, 36.10, 36.86, 37.19, 37.83,38.58 or 39.05° 2θ as depicted in FIG. 93. In a specific embodiment,L-malate salt form 4 has one, two, three, four, five, six, seven oreight characteristic X-ray powder diffraction peaks at approximately5.91, 10.91, 18.22, 18.72, 20.77, 21.22, 21.91 or 26.20° 2θ. In anotherembodiment, L-malate salt form 4 has one, two, three, four or fivecharacteristic X-ray powder diffraction peaks at approximately 5.91,10.91, 18.72, 20.77 or 21.22° 2θ. In another embodiment, L-malate saltform 4 has one, two, three, four or five characteristic X-ray powderdiffraction peaks at approximately 5.91, 10.91, 12.67, 18.72 or 20.77°2θ. In another embodiment, L-malate salt form 4 has one, two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty,twenty-one, twenty-two, twenty-three, twenty-four, twenty-five,twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one,thirty-two, thirty-three, thirty-four, thirty-five, thirty-six,thirty-seven, thirty-eight, thirty-nine, forty, forty-one, forty-two orforty-three characteristic X-ray powder diffraction peaks as set forthin Table 58.

5.19. Citrate Salt of Compound 1

In one embodiment, provided herein is a citrate salt of Compound 1.

In one embodiment, the citrate salt is a solid. In one embodiment, thecitrate salt is amorphous.

In certain embodiments, the citrate salt is prepared by evaporation of asolution comprising Compound 1 and citric acid in MTBE, MeNO₂, hexane orMeOAc.

In one embodiment, the stoichiometric ratio for Compound 1 to citricacid is about 1:1 in the citrate salt.

In certain embodiments, a solid form provided herein, e.g., a citratesalt, is substantially crystalline, as indicated by, e.g., X-ray powderdiffraction measurements. In one embodiment, the citrate salt has anX-ray powder diffraction pattern substantially as shown in FIG. 20.

In one embodiment, the citrate salt has a Raman spectrum substantiallyas depicted in FIG. 21.

5.20. Succinate Salt of Compound 1

In one embodiment, provided herein is a succinate salt of Compound 1. Incertain embodiments, the succinate salt has 3 different forms.

In one embodiment, the succinate salt is a solid. In one embodiment, thesuccinate salt is crystalline.

In certain embodiments, the succinate salt is prepared by evaporation ofa solution comprising Compound 1 and succinic acid. In one embodiment,the succinate salt is prepared by evaporation of a solution comprisingCompound 1 and succinic acid in ACN, IPA, EtOAc or acetone.

In one embodiment, succinate salt form 1 is prepared by evaporation of asolution comprising Compound 1 and succinic acid in ACN or EtOH. In oneembodiment, succinate salt form 2 is prepared by evaporation of asolution comprising Compound 1 and succinic acid in EtOAc.

In certain embodiments, solid forms, e.g., succinate salt forms 1-2, aresubstantially crystalline, as indicated by, e.g., X-ray powderdiffraction measurements. In one embodiment, succinate salt forms 1-2have X-ray powder diffraction patterns substantially as shown in FIG.22.

In one embodiment, succinate salt forms 1-2 have Raman spectrasubstantially as depicted in FIG. 23.

In certain embodiments, a solid form provided herein, e.g., succinatesalt form 1, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, succinate salt form1 has an X-ray powder diffraction pattern substantially as shown in FIG.94. In one embodiment, succinate salt form 1 has one or morecharacteristic X-ray powder diffraction peaks at approximately 5.86,8.43, 11.07, 11.79, 12.67, 13.55, 13.69, 14.47, 16.84, 17.38, 17.74,18.77, 18.97, 19.22, 20.59, 21.11, 21.33, 21.43, 21.83, 21.90, 22.23,22.78, 23.74, 23.97, 24.84, 25.12, 26.29, 27.42, 28.10, 28.20, 28.39,28.88, 29.35, 29.57, 29.82, 30.88, 31.61, 33.87, 34.33, 35.36, 39.11 or39.85° 2θ as depicted in FIG. 94. In a specific embodiment, succinatesalt form 1 has one, two, three, four, five, six, seven or eightcharacteristic X-ray powder diffraction peaks at approximately 5.86,11.79, 17.74, 18.77, 21.90, 23.74, 26.29 or 31.61° 2θ. In anotherembodiment, succinate salt form 1 has one, two, three, four or fivecharacteristic X-ray powder diffraction peaks at approximately 5.86,11.79, 23.74, 26.29 or 31.61° 2θ. In another embodiment, succinate saltform 1 has one, two, three, four or five characteristic X-ray powderdiffraction peaks at approximately 5.86, 11.79, 13.69, 21.33 or 23.74°2θ. In another embodiment, succinate salt form 1 has one, two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty,twenty-one, twenty-two, twenty-three, twenty-four, twenty-five,twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one,thirty-two, thirty-three, thirty-four, thirty-five, thirty-six,thirty-seven, thirty-eight, thirty-nine, forty, forty-one or forty-twocharacteristic X-ray powder diffraction peaks as set forth in Table 59.

In certain embodiments, a solid form provided herein, e.g., succinatesalt form 2, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, succinate salt form2 has an X-ray powder diffraction pattern substantially as shown in FIG.95. In one embodiment, succinate salt form 2 has one or morecharacteristic X-ray powder diffraction peaks at approximately 5.69,5.90, 6.18, 11.02, 16.48, 17.31, 18.49, 20.99, 22.30, 23.16, 29.01 or30.85° 2θ as depicted in FIG. 95. In a specific embodiment, succinatesalt form 2 has one, two, three, four, five, six, seven or eightcharacteristic X-ray powder diffraction peaks at approximately 5.69,5.90, 6.18, 11.02, 16.48, 18.49, 20.99 or 30.85° 2θ. In anotherembodiment, succinate salt form 2 has one, two, three, four or fivecharacteristic X-ray powder diffraction peaks at approximately 5.69,5.90, 6.18, 18.49 or 20.99° 2θ. In another embodiment, succinate saltform 2 has one, two, three, four or five characteristic X-ray powderdiffraction peaks at approximately 5.69, 6.18, 11.02, 18.49 or 20.99°2θ. In another embodiment, succinate salt form 2 has one, two, three,four, five, six, seven, eight, nine, ten, eleven or twelvecharacteristic X-ray powder diffraction peaks as set forth in Table 60.

5.21. Tosylate Salt of Compound 1

In one embodiment, provided herein is a tosylate salt of Compound 1. Incertain embodiments, the tosylate salt has 3 different forms.

In one embodiment, the tosylate salt is a solid. In one embodiment, thetosylate salt is crystalline.

In certain embodiments, the tosylate salt is prepared by evaporation ofa solution comprising Compound 1 and p-toluenesulfonic acid. In oneembodiment, the tosylate salt is prepared by evaporation of a solutioncomprising Compound 1 and p-toluenesulfonic acid in ACN, IPA, EtOAc oracetone.

In one embodiment, tosylate salt form 1 is prepared by evaporation of asolution comprising Compound 1 and p-toluenesulfonic acid in ACN. In oneembodiment, tosylate salt form 2 is prepared by evaporation of asolution comprising Compound 1 and p-toluenesulfonic acid in MeNO₂ oracetone. In one embodiment, tosylate salt form 3 is prepared byevaporation of a solution comprising Compound 1 and p-toluenesulfonicacid in EtOAc.

In certain embodiments, solid forms provided herein, e.g., tosylate saltforms 1-3, are substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, tosylate salt forms1-3 have X-ray powder diffraction patterns substantially as shown inFIG. 24.

In one embodiment, tosylate salt forms 1-3 have Raman spectrasubstantially as depicted in FIG. 25.

In certain embodiments, a solid form provided herein, e.g., tosylatesalt form 1, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, tosylate salt form 1has an X-ray powder diffraction pattern substantially as shown in FIG.96. In one embodiment, tosylate salt form 1 has one or morecharacteristic X-ray powder diffraction peaks at approximately 4.50,6.22, 8.88, 9.55, 9.67, 12.19, 13.25, 13.89, 14.86, 15.71, 17.14, 17.73,18.29, 18.63, 19.45, 19.90, 21.06, 21.71, 22.64, 23.12, 23.88, 24.27,25.43, 25.84, 26.06, 26.37, 27.71, 28.45, 28.82, 29.20, 30.62, 31.45,33.81, 34.89 or 35.38° 2θ as depicted in FIG. 96. In a specificembodiment, tosylate salt form 1 has one, two, three, four, five, six,seven or eight characteristic X-ray powder diffraction peaks atapproximately 6.22, 8.88, 12.19, 13.89, 17.14, 19.45, 21.71 or 22.64°2θ. In another embodiment, tosylate salt form 1 has one, two, three,four or five characteristic X-ray powder diffraction peaks atapproximately 6.22, 8.88, 13.89, 19.45 or 21.71° 2θ. In anotherembodiment, tosylate salt form 1 has one, two, three, four or fivecharacteristic X-ray powder diffraction peaks at approximately 6.22,8.88, 12.19, 13.89 or 21.71° 2θ. In another embodiment, tosylate saltform 1 has one, two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen,eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three,twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight,twenty-nine, thirty, thirty-one, thirty-two, thirty-three, thirty-fouror thirty-five characteristic X-ray powder diffraction peaks as setforth in Table 61.

In certain embodiments, a solid form provided herein, e.g., tosylatesalt form 2, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, tosylate salt form 2has an X-ray powder diffraction pattern substantially as shown in FIG.97. In one embodiment, tosylate salt form 2 has one or morecharacteristic X-ray powder diffraction peaks at approximately 5.78,6.24, 6.48, 7.01, 8.13, 9.79, 11.67, 12.04, 12.60, 14.25, 15.04, 15.57,16.42, 17.53, 18.13, 18.31, 18.89, 19.55, 19.90, 21.36, 21.61, 21.94,22.49, 22.74, 23.05, 23.35, 23.59, 24.36, 24.55, 25.53, 25.78, 26.54,27.40, 28.07, 28.49, 29.32, 30.44, 32.58, 33.16, 33.62, 35.52 or 36.88°2θ as depicted in FIG. 97. In a specific embodiment, tosylate salt form2 has one, two, three, four, five, six, seven or eight characteristicX-ray powder diffraction peaks at approximately 6.24, 6.48, 8.13, 11.67,15.04, 18.31, 18.89 or 23.59° 2θ. In another embodiment, tosylate saltform 2 has one, two, three, four or five characteristic X-ray powderdiffraction peaks at approximately 6.24, 8.13, 11.67, 15.04 or 18.31°2θ. In another embodiment, tosylate salt form 2 has one, two, three,four or five characteristic X-ray powder diffraction peaks atapproximately 5.78, 6.24, 6.48, 8.13 or 21.36° 2θ. In anotherembodiment, tosylate salt form 2 has one, two, three, four, five, six,seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen,sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two,twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven,twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three,thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight,thirty-nine, forty, forty-one or forty-two characteristic X-ray powderdiffraction peaks as set forth in Table 62.

In certain embodiments, a solid form provided herein, e.g., tosylatesalt form 3, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, tosylate salt form 3has an X-ray powder diffraction pattern substantially as shown in FIG.98. In one embodiment, tosylate salt form 3 has one or morecharacteristic X-ray powder diffraction peaks at approximately 5.59,7.44, 8.91, 11.22, 13.13, 13.78, 14.05, 14.89, 15.62, 17.78, 18.15,19.24, 19.70, 20.77, 21.72, 21.96, 22.40, 23.49, 24.97, 25.97, 26.66,28.92 or 31.46° 2θ as depicted in FIG. 98. In a specific embodiment,tosylate salt form 3 has one, two, three, four, five, six, seven oreight characteristic X-ray powder diffraction peaks at approximately5.59, 11.22, 13.13, 17.78, 18.15, 20.77, 21.96 or 22.40° 2θ. In anotherembodiment, tosylate salt form 3 has one, two, three, four or fivecharacteristic X-ray powder diffraction peaks at approximately 5.59,11.22, 18.15, 20.77 or 22.40° 2θ. In another embodiment, tosylate saltform 3 has one, two, three, four or five characteristic X-ray powderdiffraction peaks at approximately 5.59, 7.44, 11.22, 18.15 or 20.77°2θ. In another embodiment, tosylate salt form 3 has one, two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty,twenty-one, twenty-two or twenty-three characteristic X-ray powderdiffraction peaks as set forth in Table 63.

5.22. Mesylate Salt of Compound 1

In one embodiment, provided herein is a mesylate salt of Compound 1. Incertain embodiments, the mesylate salt has 2 different forms.

In one embodiment, the mesylate salt is a solid. In one embodiment, themesylate salt is crystalline.

In certain embodiments, the mesylate salt provided herein is prepared byevaporation of a solution comprising Compound 1 and methanesulfonicacid. In one embodiment, the mesylate salt is prepared by evaporation ofa solution comprising Compound 1 and methanesulfonic acid in ACN/IPA,EtOH/IPA, EtOAc or acetone.

In one embodiment, mesylate salt form 1 is prepared by evaporation of asolution comprising Compound 1 and methanesulfonic acid in ACN/IPA,EtOH/IPA or acetone. In one embodiment, mesylate salt form 2 is preparedby evaporation of a solution comprising Compound 1 and methanesulfonicacid in EtOAc.

In certain embodiments, solid forms provided herein, e.g., mesylate saltforms 1-2, are substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, mesylate salt forms1-2 have X-ray powder diffraction patterns substantially as shown inFIG. 26.

In one embodiment, mesylate salt forms 1-2 have Raman spectrasubstantially as depicted in FIG. 27.

In certain embodiments, a solid form provided herein, e.g., mesylatesalt form 1, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, mesylate salt form 1has an X-ray powder diffraction pattern substantially as shown in FIG.99. In one embodiment, mesylate salt form 1 has one or morecharacteristic X-ray powder diffraction peaks at approximately 5.78,7.87, 10.30, 10.71, 11.61, 11.86, 12.39, 13.50, 13.83, 14.17, 15.05,15.56, 15.80, 16.29, 17.06, 17.49, 17.74, 18.10, 18.30, 18.54, 19.25,19.89, 20.18, 20.58, 20.98, 21.56, 21.95, 23.41, 24.22, 24.82, 25.53,26.08, 26.77, 27.27, 28.17, 28.38, 29.03, 29.31, 29.87, 30.81, 32.02,32.99, 34.03, 35.01, 35.45, 35.72, 36.33 or 37.65° 2θ as depicted inFIG. 99. In a specific embodiment, mesylate salt form 1 has one, two,three, four, five, six, seven or eight characteristic X-ray powderdiffraction peaks at approximately 5.78, 10.71, 11.61, 17.49, 18.10,18.30, 18.54 or 23.41° 2θ. In another embodiment, mesylate salt form 1has one, two, three, four or five characteristic X-ray powderdiffraction peaks at approximately 5.78, 10.71, 11.61, 18.10 or 23.41°2θ. In another embodiment, mesylate salt form 1 has one, two, three,four or five characteristic X-ray powder diffraction peaks atapproximately 5.78, 7.87, 10.71, 18.10 or 19.25° 2θ. In anotherembodiment, mesylate salt form 1 has one, two, three, four, five, six,seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen,sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two,twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven,twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty-three,thirty-four, thirty-five thirty-six, thirty-seven, thirty-eight,thirty-nine, forty, forty-one, forty-two, forty-three, forty-four,forty-five, forty-six, forty-seven or forty-eight characteristic X-raypowder diffraction peaks as set forth in Table 64.

In certain embodiments, a solid form provided herein, e.g., mesylatesalt form 2, is substantially crystalline, as indicated by, e.g., X-raypowder diffraction measurements. In one embodiment, mesylate salt form 2has an X-ray powder diffraction pattern substantially as shown in FIG.100. In one embodiment, mesylate salt form 2 has one or morecharacteristic X-ray powder diffraction peaks at approximately 5.14,5.26, 10.45, 16.37, 18.36, 20.41, 20.95, 21.59, 21.86, 22.14, 22.63,23.33, 24.24, 25.76, 26.16, 28.41 or 31.70° 2θ as depicted in FIG. 100.In a specific embodiment, mesylate salt form 2 has one, two, three,four, five, six, seven or eight characteristic X-ray powder diffractionpeaks at approximately 5.14, 5.26, 10.45, 18.36, 20.41, 20.95, 21.59 or26.16° 2θ. In another embodiment, mesylate salt form 2 has one, two,three, four or five characteristic X-ray powder diffraction peaks atapproximately 5.14, 5.26, 10.45, 18.36 or 20.95° 2θ. In anotherembodiment, mesylate salt form 2 has one, two, three, four or fivecharacteristic X-ray powder diffraction peaks at approximately 5.14,10.45, 18.36, 20.41 or 20.95° 2θ. In another embodiment, mesylate saltform 2 has one, two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, fifteen, sixteen or seventeencharacteristic X-ray powder diffraction peaks as set forth in Table 65.

5.23. Besylate Salt of Compound 1

In one embodiment, provided herein is a besylate salt of Compound 1.

In one embodiment, the besylate salt is a solid. In one embodiment, thebesylate salt is crystalline.

In certain embodiments, the besylate salt provided herein is prepared byevaporation of a solution comprising Compound 1 and benzenesulfonicacid. In one embodiment, the besylate salt is prepared by evaporation ofa solution comprising Compound 1 and benzenesulfonic acid in MeNO₂.

In certain embodiments, a solid form provided herein, e.g., a besylatesalt, is substantially crystalline, as indicated by, e.g., X-ray powderdiffraction measurements. In one embodiment, the besylate salt has anX-ray powder diffraction pattern substantially as shown in FIG. 28.

In one embodiment, a besylate salt has a Raman spectrum substantially asdepicted in FIG. 29.

In certain embodiments, a solid form provided herein, e.g., besylatesalt, is substantially crystalline, as indicated by, e.g., X-ray powderdiffraction measurements. In one embodiment, besylate salt has an X-raypowder diffraction pattern substantially as shown in FIG. 101. In oneembodiment, besylate salt has one or more characteristic X-ray powderdiffraction peaks at approximately 6.29, 7.84, 9.64, 11.32, 12.63,14.38, 15.89, 16.81, 17.44, 19.09, 19.39, 19.82, 20.31, 20.79, 21.63,22.35, 22.82, 23.87, 25.30, 26.12, 27.64, 28.94 or 34.90° 2θ as depictedin FIG. 101. In a specific embodiment, besylate salt has one, two,three, four, five, six, seven or eight characteristic X-ray powderdiffraction peaks at approximately 6.29, 9.64, 11.32, 14.38, 19.39,20.79, 23.87 or 27.64° 2θ. In another embodiment, besylate salt has one,two, three, four or five characteristic X-ray powder diffraction peaksat approximately 6.29, 11.32, 14.38, 19.39 or 23.87° 2θ. In anotherembodiment, besylate salt has one, two, three, four or fivecharacteristic X-ray powder diffraction peaks at approximately 6.29,7.84, 11.32, 14.38 or 20.79° 2θ. In another embodiment, besylate salthas one, two, three, four, five, six, seven, eight, nine, ten, eleven,twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen,nineteen, twenty, twenty-one, twenty-two or twenty-three characteristicX-ray powder diffraction peaks as set forth in Table 66.

5.24. Fumarate Salt of Compound 1

In one embodiment, provided herein is a fumarate salt of Compound 1.

In one embodiment, the fumarate salt is a solid. In one embodiment, thefumarate salt is crystalline. In one embodiment, the fumarate salt is ahemi-fumarate salt.

In certain embodiments, the fumarate salt is prepared by evaporation ofa solution comprising Compound 1 and fumaric acid. In one embodiment,the fumarate salt is prepared by evaporation of a solution comprisingCompound 1 and fumaric acid in ACN.

In one embodiment, the stoichiometric ratio for Compound 1 to fumaricacid is about 2:1 in the fumarate salt.

In certain embodiments, a solid form provided herein, e.g., a fumaratesalt, is substantially crystalline, as indicated by, e.g., X-ray powderdiffraction measurements. In one embodiment, the fumarate salt has anX-ray powder diffraction pattern substantially as shown in FIG. 28.

In one embodiment, a fumarate salt has a Raman spectrum substantially asdepicted in FIG. 29.

In certain embodiments, a solid form provided herein, e.g., fumaratesalt, is substantially crystalline, as indicated by, e.g., X-ray powderdiffraction measurements. In one embodiment, fumarate salt has an X-raypowder diffraction pattern substantially as shown in FIG. 102. In oneembodiment, fumarate salt has one or more characteristic X-ray powderdiffraction peaks at approximately 5.97, 8.31, 11.09, 11.92, 12.38,12.97, 13.53, 14.72, 15.81, 16.66, 18.51, 18.92, 20.94, 21.36, 21.76,22.34, 23.33, 24.08, 24.65, 25.58, 26.31, 28.74, 29.20, 29.83, 30.96,31.72, 34.86 or 36.34° 2θ as depicted in FIG. 102. In a specificembodiment, fumarate salt has one, two, three, four, five, six, seven oreight characteristic X-ray powder diffraction peaks at approximately5.97, 11.09, 18.92, 21.36, 21.76, 26.31, 28.74 or 31.72° 2θ. In anotherembodiment, fumarate salt has one, two, three, four or fivecharacteristic X-ray powder diffraction peaks at approximately 5.97,11.09, 21.36, 21.76 or 26.31° 2θ. In another embodiment, fumarate salthas one, two, three, four or five characteristic X-ray powderdiffraction peaks at approximately 5.97, 8.31, 11.09, 20.94 or 24.08°2θ. In another embodiment, fumarate salt has one, two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one,twenty-two, twenty-three, twenty-four, twenty-five, twenty-six,twenty-seven or twenty-eight characteristic X-ray powder diffractionpeaks as set forth in Table 67.

6. EXAMPLES

The following Examples are presented by way of illustration, notlimitation. The following abbreviations are used in descriptions andexamples:

-   ACN: Acetonitrile-   DSC: Differential Scanning Calorimetry-   DVS: Dynamic Vapor Sorption-   EtOAc: Ethyl acetate-   EtOH: Ethanol-   HPLC: High performance liquid chromatography-   IPA: Isopropanol-   MeNO₂: Nitromethane-   MeOH: Methanol-   mp: Melting point-   MTBE: tert-Butyl methyl ether-   NMR: Nuclear magnetic resonance-   RH: Relative Humidity-   SGF: Simulated Gastric Fluid (without Pepsin)-   XRPD: X-Ray Powder Diffraction

Certain compositions comprising Compound A were prepared and tested fora number of physical and chemical properties. Modifications were thenmade and subsequent formulations were also tested, until formulationspossessing desirable physical and chemical properties were found. Thefollowing example describes these formulations and their testing.

6.1. Formulation A

Table 1 provides a dosage formulation for a 100 mg strength Compound 1single unit dose (Formulation A).

TABLE 1 Formulation A Percent Amount Amount Per Tablet Per Tablet PerBatch Ingredients (%) (mg) (g) Intragranular Compound 1 28.57 100.0285.71 Microcrystalline 29.43 103.01 294.3 Cellulose (Avicel PH101)Mannitol 26 91.00 260.0 (Mannitol 200) Ac-Di-Sol (Portion 1) 2 7.0020.00 HPMC 3 cps 3 10.50 30.00 (Methocel K3) Water, USP, 0 NA 0 *(570.0)Extragranular Microcrystalline 8 28.00 80.00 Cellulose (Avicel PH102)Ac-Di-Sol (Portion 2) 2 7.00 20.00 Magnesium Stearate 1 3.5 10.00 TotalCore Tablet 100 350.0 1000 *Amount of purified water, USP, dispensed,based on 5% granulation solution.

The process for preparation of Formulation A comprised the steps of:

a) Weighing out excipients.

b) Weighing out API.

c) Preparing granulation binder solution (5%).

d) Preparing 570 g of purified water, USP, by heating it to −70° C.

e) Slowly dispersing 30 g of HPMC into the water while mixing andcontinued mixing until material was fully dissolved.

f) Passing the Compound 1, Avicel 101, Mannitol 200 and Ac-Di-Sol(Portion 1) through an 18/20 mesh Screen.

g) Loading Compound 1, Avicel 101, Mannitol 200 and Ac-Di-Sol(Portion 1) into the KG5 Granulator, equipped with an appropriate sizedbowl and dry mix for 10 minutes.

h) Equipping the KG5 with a spray tip and peristaltic tubing sufficientto produce an adequate spray rate that allowed for consistentapplication of the granulation binder solution. Adding additional wateras needed.

i) Wetting mass material sufficiently to ensure that granulationappeared visually consistent throughout the bowl.

j) Discharging the wet mass from the granulator and transferring to theexpansion chamber of the GPCG-1 Fluid Bed Granulator. Dry until anendpoint of <2 Loss on Drying was achieved.

TABLE 2 DRYING PROCESS Start Up Parameters* Initial Inlet Air-Volume20-35 CFM Inlet Temp. Set Point 70° C. Inlet Temp. Target 60-80° C.Product Temp Target 40-60° C. Initial Inlet Air-Volume 20-35 CFM InletTemp. Set Point 70° C. *May be changed as needed to achieve proper bedcharacteristics.

k) Milling the dried granules using the Comil, fitted with anappropriate screen (0.075R).

l) Performing bulk/tap density tests and particle size distributionanalysis. After the tests were complete, returning the test materials tomilled granulation.

m) Obtaining a net weight for the milled granule.

n) Calculating yield percentage through milling.

o) Re-calculating and re-weighing the extra-granular excipientsaccording to the yield in Step n.

p) Passing the Avicel 102 and Ac-Di-Sol (Portion 2) through an 18/20mesh Screen.

q) Combining the milled granulation with the screened Avicel 102 andAc-Di-Sol into an appropriate sized V-shell blender and blending for 100revolutions (adjusting blender speed to achieve desired blend time).

r) Passing the magnesium stearate through a 30 mesh screen.

s) Adding the screened magnesium stearate to the blender and blendingfor 50 revolutions (adjusting blender speed to achieve desired blendtime).

t) Discharging the blend into a suitable container and labelingappropriately. Performing bulk/tap density tests and particle sizedistribution analysis. After the tests were completed, returning thetest materials to final blend material.

u) Setting up compress stations of the Compacta tablet press usingselected tooling.

v) Adjusting the tablet press until the following specifications inTable 3 for tablet weights were met. Ensuring that initial tabletphysicals were acceptable, (i.e., friability less than 0.3% withoutcapping), before proceeding with compressing. Hardness, tablet thicknessand disintegration times were measured and documented.

w) Compressing tablets and collect acceptable core tablets in a tintedcontainer, double lined with polyethylene bags.

TABLE 3 Individual Tablet Weights Mean Tablet Weights Upper Limit (+7%)374.5 mg Upper Limit (+5%) 367.5 mg Upper Control Limit 367.5 mg UpperControl 357.0 mg (+5%) Limit (+2%) Target 350.0 mg Target 350.0 mg LowerControl Limit 332.5 mg Lower Control 343.0 mg (−5%) Limit (−2%) LowerLimit (−7%) 325.5 mg Lower Limit (−5%) 332.5 mg

Friability tests were performed on 10 tablets at the beginning of thecompression run and on a 10 tablet composite sample after the batch wascompleted. The apparatus and method were defined in the USP/NF <1216>and in SOP PHARM 0008. Specification—weight loss was less than 0.3%without capping.

Disintegration time tests were performed on 6 samples at the beginningof the compression run, and on a 6 tablet composite sample after thebatch was completed. The apparatus and method were defined in the USP/NF<701> with one disk.

Hardness tests were performed on 10 samples taken at the beginning,middle, and end of the compression run. The hardness of 10 tablets wasmeasured and the average was calculated.

Thickness tests were performed on a 10 tablet sample taken at theBeginning of the run and on 10 tablets of a composite sample after therun is completed. The thickness of 10 tablets was measured and anaverage was calculated.

Weighing 10 tablets individually at the beginning, middle, and end ofrun. Recording weights to 0.1 mg. Acceptance Criteria: +/−7% oftheoretical tablet weight (350.0 mg). Acceptance limit: 325.5-374.5 mg.

10 tablets were sampled and weighed together at the beginning, middle,and end of run, and an average tablet weight (ATW) was calculated.Record ATW to 0.1 mg. Acceptance Criteria: Mean weight of 10 tabletsmust be within +/−5% of theoretical. Average tablet weight (350.0 mg).Acceptance limit: 332.5-367.5 mg.

6.2. Formulation B

Table 4 provides a dosage formulation for a 100 mg strength Compound 1single unit dose (Formulation B).

The process for preparation of Formulation B comprises the same steps inthe preparation of Formulation A.

TABLE 4 Formulation B Percent Amount Amount Per Tablet Per Tablet PerBatch Ingredients (%) (mg) (g) Intragranular Compound 1 28.57 100.0285.71 Microcrystalline 25.43 89.01 254.3 Cellulose (Avicel PH101)Mannitol 26 91.00 260.0 (Mannitol 200) Ac-Di-Sol (Portion 1) 4 14.0040.00 HPMC 3 cps 3 10.50 30.00 (Methocel K3) Water, USP, 0 NA 0 *(570.0)Extragranular Microcrystalline 8 28.00 80.00 Cellulose (Avicel PH102)Ac-Di-Sol (Portion 2) 4 14.00 40.00 Magnesium Stearate 1 3.5 10.00 TotalCore Tablet 100 350.0 1000 *Amount of purified water, USP, dispensed,based on 5% granulation solution.

6.3. Formulation C

Table 5 provides a dosage formulation for a 100 mg strength Compound 1single unit dose (Formulation C).

The process for preparation of Formulation C comprises the same steps inthe preparation of Formulation A.

TABLE 5 Formulation C Percent Amount Amount Per Tablet Per Tablet PerBatch Ingredients (%) (mg) (g) Intragranular Compound 1 28.57 100.0285.71 Microcrystalline 23.93 83.76 239.3 Cellulose (Avicel PH101)Mannitol 26 91.00 260.0 (Mannitol 200) Ac-Di-Sol (Portion 1) 4 14.0040.00 HPMC 3 cps 4.5 15.75 45.00 (Methocel K3) Water, USP, 0 NA 0*(570.0) Extragranular Microcrystalline 8 28.00 80.00 Cellulose (AvicelPH102) Ac-Di-Sol (Portion 2) 4 14.00 40.00 Magnesium Stearate 1 3.510.00 Total Core Tablet 100 350.0 1000 *Amount of purified water, USP,dispensed, based on 5% granulation solution.

6.4. Formulation D

Table 6 provides a dosage formulation for a 100 mg strength Compound 1single unit dose (Formulation D).

The process for preparation of Formulation D comprises the same steps inthe preparation of Formulation A.

TABLE 6 Formulation D Percent Amount Amount Per Tablet Per Tablet PerBatch Ingredients (%) (mg) (g) Intragranular Compound 1 28.57 100.0285.71 Microcrystalline 27.93 97.76 279.3 Cellulose (Avicel PH101)Mannitol 26 91.00 260.0 (Mannitol 200) Ac-Di-Sol (Portion 1) 2 7.0020.00 HPMC 3 cps 4.5 15.75 45.00 (Methocel K3) Water, USP, 0 NA 0*(570.0) Extragranular Microcrystalline 8 28.00 80.00 Cellulose (AvicelPH102) Ac-Di-Sol (Portion 2) 2 7.00 20.00 Magnesium Stearate 1 3.5 10.00Total Core Tablet 100 350.0 1000 *Amount of purified water, USP,dispensed, based on 5% granulation solution.

6.5. Formulation Development

Objective: The objective of this exercise was to provide confirmation ofscalability of the Compound 1 common blend granulation process,previously used for the 100 mg dosage form development and to evaluatethe 30 mg and 200 mg dosage form compression and coating processes. Theprimary purposes, of these experiments, were to acquire technicalknowledge, in preparation for the subsequent CTM manufacturing, of allthree strengths.

Development: In order to allow for a range of 30 mg-200 mg dosage forms,while producing a common granulation, the following formulation in Table7 was selected as the basis for this exercise.

TABLE 7 Percent Amount Per Batch Per Batch Ingredients (%) (g) Compound1 Drug Substance 28.57 1428.5 Microcrystalline Cellulose 25.43 1271.5(Avicel PH101) Mannitol 26 1300 Pearlitol (200) Ac-Di-Sol (Portion 1) 4200.0 HPMC 3 cps 3 150.0 (Methocel K3) Microcrystalline Cellulose 8400.0 (Avicel PH102) Ac-Di-Sol (Portion 2) 4 200.0 Magnesium Stearate 150.00 Total Core Tablet 100 5000

Based on this 28.57% Compound 1 loading within a common granulation,three discreet dosage forms were prepared, to meet the followingspecifications in Table 8.

TABLE 8 Tablet Product Weight Dimensions Shape Color Embossing Compound1, 105.0 mg 0.25″ Round/Standard Yellow None  30 mg Tablet ConcaveCompound 1, 350.0 mg 0.2220″ × 0.5720″ Modified White None 100 mg TabletCapsule/Standard Concave Compound 1, 700.0 mg 0.6693″ × 0.3937″Oval/Standard Brown None 200 mg Tablet Concave

The processes and equipments for wet granulation process are provided inFIG. 1.

Granulation: First, 5% binder solution was prepared comprising 1)heating 2850 g of purified water, USP to 70° C.; 2) dispersing 150 g ofHypromelose 3 cps (Methocel K3) into the water; and 3) mixing untildissolved. Second, intragranular material was screened by 20 meshscreen, which includes Compound 1, microcrystalline cellulose (Avicel101), mannitol (pearlitol 200) and croscarmellose sodium (Ac-Di-Sol)portion 1. Third, granulation process was performed in PMA Granulator 25Liter bowl according to the parameters in Table 9 and Table 10.

TABLE 9 Granulation Parameters for Lot 1 Elapsed Impeller Chopper ~SprayPower Amount Time Speed Speed Rate Con- Step (g) (mm:ss) (RPM) (RPM)(gpm) sumption Mix N/A 10:00 Low *Low/Off N/A 9 Binder 3000 36:00 LowLow 83 9 Addition Mix N/A  1:00 Low Off N/A 9 Mix N/A  1:00 Low Low N/A9 *Stopped chopper approx. 15 minutes into binder addition.

TABLE 10 Granulation Parameters for Lot 2 Elapsed Impeller Chopper~Spray Power Amount Time Speed Speed Rate Con- Solution (g) (mm:ss)(RPM) (RPM) (gpm) sumption Mix N/A 10:00 Low Off N/A 9 Binder 3000 36:00Low Low 83 9 Addition Mix N/A  1:00 Low Off N/A 9 Mix N/A  1:00 Low LowN/A 9

The drying process was performed in O'Hara FBD with 45 L bowl accordingto the parameters in Table 11, Table 12 and Table 13.

TABLE 11 Start Up Parameters Initial Inlet Air-Volume TBD Inlet Temp.Set Point 70° C. Inlet Temp. Target 60-80° C. Product Temp Target 40-60°C.

TABLE 12 Drying Parameters for Lot 1 Inlet Inlet Inlet Time Air Temp.Set Temp. Product Elapsed Vol Point Actual Temp Step (hh:min) CFM (° C.)(° C.) (° C.) Comments Dry 00:00 700 70 27 22 37.50% Initial LOD Dry15:00 800 60 55 30 14.05% LOD Dry 30:00 1000 70 67 49 1:00% LOD (0.95%From Bowl)

TABLE 13 Drying Parameters for Lot 2 Inlet Inlet Inlet Time Air Temp.Set Temp. Product Elapsed Vol Point Actual Temp Step (hh:min) CFM (° C.)(° C.) (° C.) Comments Dry 00:00 1000 70 32 34 36.50% Initial LOD Dry15:00 1000 70 70 40 3.05% LOD Dry 22:00 1000 70 70 40 0.95% LOD (0.95%From Bowl)

After the mixture was screened with Screen 075R050 (0.075″), the mixturewas milled at 1400 RPM.

The amount of the extragranular excipients including microcrystallinecellulose (Avicel 102) and croscarmellose sodium (Ac-Di-Sol) portion 2was adjusted in proportion to milled granule yield. Then theextragranular excipients were screened with 20 mesh screen.

The milled material and extragranular excipients were blended in a 16 QtV-Shell Blender for 4 minutes at 30 RPM (120 revolutions).

The magnesium stearate was screened with 30 mesh screen and then wasblended with the milled material and extragranular excipients in a 16 QtV-Shell blender for 2 minutes at 30 RPM (60 revolutions).

The analytical data for the granulated material is provided below inTable 14, Table 15 and Table 16.

TABLE 14 Milled Granule Bulk & Tapped Density MILLED FINAL BATCH TESTGRANULE BLEND Lot 1 Average Bulk 0.53 0.56 Density Average 0.60 0.65Tapped Density Average Carr 13 15 Index Lot 2 Average Bulk 0.56 0.59Density Average 0.65 0.68 Tapped Density Average Carr 15 14 Index

TABLE 15 Milled Granule Particle Size Analysis-Lot 1 Milled GranuleFinal Blend Screen size % Retained % Retained  30 mesh 33.7 10.0  40mesh 12.5 12.5  60 mesh 37.6 48.7  80 mesh 9.1 13.0 100 mesh 1.7 3.6 200mesh 3.0 6.2 Fines 2.4 5.7

TABLE 16 Milled Granule Particle Size Analysis-Lot 2 Milled GranuleFinal Blend Screen size % Retained % Retained  30 mesh 8.3 7.4  40 mesh6.9 7.4  60 mesh 46.0 42.0  80 mesh 22.5 20.2 100 mesh 5.1 5.0 200 mesh9.2 10.2 Fines 0.6 7.7

Prior each compression event, a minimum of three compression forces wereevaluated to determine which would provide optimal tablet physicalcharacteristics on the Compacta tablet press. Results of this evaluationare provided below in Table 17.

TABLE 17 Min. Max. Average Individual Individual Compression AverageTablet Average Tablet Tablet Force Friability Disintegration ThicknessHardness Weight Weight Batch Force (kN) (% Loss) (mm:ss) (mm) (kP) (mg)(mg) Lot 1 A 8 0.17 06:13 3.56 5.7 107.2 110.0 (30 mg B 11 0.15 06:323.51 6.0 106.8 111.2 tablets) C 16 0.39 02:23 3.63 3.9 105.0 107.2 Lot 2A 11 0.22 04:58 4.86 11.7 344.5 351.6 (100 mg B 13 0.18 07:13 4.74 13.7342.7 346.0 tablets) C 8 0.30 02:43 5.11 6.9 344.8 349.5 D 15 0.12 08:524.75 14.3 352.1 353.3 Lot 2 A 20 0.19 04:03 5.69 9.5 695.0 702.6 (200 mgB 25 0.17 05:20 5.62 10.5 695.2 702.4 tablets) C 30 0.12 07:46 5.54 10.2695.1 704.8 D 35 0.12 08:32 5.51 12.3 694.8 703.3

Compound 1 30 mg tablets were prepared on Compacta B-D tablet press with0.25″ standard round concave plain/plain tooling, 7 stations and targetfriablity<0.3% without capping. The target tablet weights are providedin Table 18.

TABLE 18 Individual Tablet Weights Mean Tablet Weights Upper Limit (+7%)115.5 mg Upper Limit (+5%) 110.3 mg Upper Control 110.3 mg Upper Control107.1 mg Limit (+5%) Limit (+2%) Target 105.0 mg Target 105.0 mg LowerControl  99.7 mg Lower Control 102.9 mg Limit (−5%) Limit (-2%) LowerLimit (−7%)  94.5 mg Lower Limit (−5%)  99.7 mg

Compound 1 100 mg Tablets were prepared on Compacta B-D tablet presswith 0.2220″×0.5720″ modified standard concave plain/plain tooling, 4stations, and target friablity<0.3% without capping. The target tabletweights are provided in Table 19.

TABLE 19 Individual Tablet Weights Mean Tablet Weights Upper Limit (+7%)374.5 mg Upper Limit (+5%) 367.5 mg Upper Control 367.5 mg Upper Control357.0 mg Limit (+5%) Limit (+2%) Target 350.0 mg Target 350.0 mg LowerControl 332.5 mg Lower Control 343.0 mg Limit (−5%) Limit (−2%) LowerLimit (−7%) 325.5 mg Lower Limit (−5%) 332.5 mg

Compound 1 200 mg tablets were prepared on Compacta B-D tablet presswith 0.6693″×0.3937″ standard concave plain/plain tooling, 4 stationsand target friablity<0.3% without capping. The target tablet weights areprovided in Table 20.

TABLE 20 Individual Tablet Weights Mean Tablet Weights Upper Limit (+7%)749.0 mg Upper Limit (+5%) 735.0 mg Upper Control 735.0 mg Upper Control714.0 mg Limit (+5%) Limit (+2%) Target 700.0 mg Target 700.0 mg LowerControl 665.0 mg Lower Control 686.0 mg Limit (−5%) Limit (−2%) LowerLimit (−7%) 651.0 mg Lower Limit (−5%) 665.0 mg

In-process compression test results are provided in Table 21.

TABLE 21 Min. Max. Avg Avg Individual Individual Weight Avg AvgFriability Avg Dis- Tablet Tablet of 10 Hardness Thickness (%integration Weight Weight Tablets Interval (kP) (mm) Loss) (mm:ss) (mg)(mg) (mg) Lot 1 Initial 5.4 3.50 0.16 06:05: 104.3 109.2 109.7 (30 mgMid 4.8 N/A N/A N/A 102.3 104.9 103.2 tablets) End/Composite 4.2 3.410.11 05:19 101.6 106.6 104.0 Lot 2 Initial 12.5 4.81 0.14 07:40 347.5353.3 345.8 (100 mg Mid 11.7 N/A N/A N/A 354.0 359.6 350.8 tablets)End/Composite 11.2 4.77 0.17 06:29 352.4 357.9 347.4 Lot 2 Initial 10.55.55 0.16 07:15 699.0 705.8 701.6 (200 mg Mid 9.7 N/A N/A N/A 697.3705.4 699.6 tablets) End/Composite 9.9 5.56 0.10 07:00 695.8 705.1 698.6

Film Coating:

Compound 1 30 mg tablets were coated with Opadry yellow (03B12885) in15% solids coating suspension. The minimum suspension mix time was 45minutes. The tablets had about 3% weight gain after coating. Coating panload was 1358 g. Coater used was O'Hara Labcoat II w/12″ Pan.

The film-coat was applied to the pre-warmed core tablets in the O'Haracoating pan to a weight gain of approximately 3% as follows (recordin-process data in table below at least every 15 minutes):

a) Mean pre-warmed tablet weight (from step 5)=104.4 mg

b) Desired target weight (3% weight gain)=6a*1.03)=107.5 mg

c) Target supply temp=60° C. (may be adjusted to maintain nominalexhaust temp.)

d) Target air flow (cfm)=60-120

Atomization air psi: 19; pattern air psi: 19; gun distance: 4″

TABLE 22 Supply Mean Temp Exhaust Air Spray Pan Tab Wt. Time Set/actualTemp Flow Rate Speed (n = 100) (hh:mm) (° C.) (° C.) (cfm) (g/min) (RPM)(mg) 15:30 60/60 39.6 110 5 20 104.4 15:44 60/60 41.4 120 15 20 105.616:00 60/60 40.0 120 13 20 107 16:10 60/60 41.0 120 14 20 107.6

e) Record the final mean Opadry coated tablet weight: 107.6 mg.

Compound 1 100 mg tablets were coated with Opadry white (YS-1-18202-A)in 15% solids coating suspension. The minimum suspension mix time was 45minutes. The tablets had about 3% weight gain after coating. Coating panload was 2487 g. Coater used was O'Hara labcoat II w/15″ pan.

The film-coat was applied to the pre-warmed core tablets in the O'Haracoating pan to a weight gain of approximately 3% as follows (recordin-process data in table below at least every 15 minutes):

a) Mean pre-warmed tablet weight (from step 5)=349.9 mg

b) Desired target weight (3% weight gain)=6a*1.03=360.4 mg

c) Target supply temp=60° C. (may be adjusted to maintain nominalexhaust temp.)

d) Target Air flow (cfm)=60-120

Atomization air psi: 20; pattern air psi: 20; gun distance: 5″

TABLE 23 Supply Mean Tab Temp Exhaust Air Spray Pan Wt. Time Set/actualTemp Flow Rate Speed (n = 100) (hh:mm) (° C.) (° C.) (cfm) (g/min) (RPM)(mg) 00:00   60/59.7 35 140 14 13 349.9 00:15 68/68 42 170 15 18 353.500:30 60/60 42 175 14 18 358.4 00:35 60/60 42 175 14 18 360.5

e) Record the final mean Opadry coated tablet weight: 360.5 mg.

Compound 1 200 mg tablets were coated with Opadry brown (03B16878) in15% solids coating suspension. The minimum suspension mix time was 45minutes. The tablets had about 3% weight gain after coating. Coating panload was 4252 g. Coater used was O'Hara labcoat II w/19″ pan.

The film-coat was applied to the pre-warmed core tablets in the O'Haracoating pan to a weight gain of approximately 3% as follows (recordin-process data in table below at least every 15 minutes):

a) Mean pre-warmed tablet weight (from step 5)=698.9 mg

b) Desired target weight (3% weight gain)=6a*1.03=719.9 mg

c) Target supply temp=60° C. (may be adjusted to maintain nominalexhaust temp.)

d) Target air flow (cfm)=60-120

Atomization air psi: 20; pattern air psi: 20; gun distance: 5″

TABLE 24 Supply Mean Tab Temp Exhaust Air Spray Wt. Time Set/actual TempFlow Rate Pan Speed (n = 100) (hh:mm) (° C.) (° C.) (cfm) (g/min) (RPM)(mg) 00:00 60/59 39 175 20 15 698.9 00:15 67/67 42 175 20 15 706.5 00:3067/67 43 175 20 15 709.6 00:45 63/63 43 175 20 15 717.4 00:55 63/63 43175 20 15 720.0

e) Record the final mean Opadry coated tablet weight: 360.5 mg.

FIG. 2 depicts dissolution profiles of Compound 1 tablets in 0.1 N HCl.

FIG. 3 depicts dissolution profiles of Compound 1 tablets in 0.01 N HCl.

FIG. 4 depicts dissolution profiles of Compound 1 tablets in an aqueoussolution with pH 4.5.

6.6. Protocol of Dog Pharmacokinetic Studies

A total of 4 male beagle dogs (as close to 10 kg as possible) wereassigned to study. For each phase, all animals were fasted for at least8 hours prior to dosing and through the first 4 hours of blood samplecollection (food was returned within 30 minutes following collection ofthe last blood sample at the 4 hour collection interval, whereapplicable). Total fasting time did exceed 24 hours.

Phase 1: Each animal in Group 1 received a single capsule dose ofCompound 1 as outlined in the table below.

Phase 2: Following a washout of approximately 5 days, each animal inGroup 1 received a single tablet dose of Compound 1 as outlined in thetable below.

TABLE 25 Dose Test Number Dose Level Dose Collection Group Article ofMales Route Vehicle (mg/kg) Volume Intervals Phase 1 1 Cmpd 1 4 OralCapsule^(A) 100 1 capsule Blood^(B) capsule per animal Phase 2 1 Cmpd 14 Oral Tablet^(A) 100 1 tablet per Blood^(B) tablet animal ^(A)Allcapsule/tablet formulations were provided pre-formulated and were usedas received. ^(B)Blood samples were collected predose and at 0.5 (30min.), 1, 2, 4, 8, 12, and 24 hours postdose, and processed for plasma.

TABLE 26 Pharmacokinetic Blood Collection Blood Collection Volume: 1mL/sample Anticoagulant K₂EDTA Site of Collection Jugular Sample Plasmasamples were stored frozen at −60 to Storage −90° C. until shipment.

TABLE 27 Antemortem Evaluations Cageside All animals were observed atleast twice a day Observations for morbidity, mortality, injury, andavailability of food and water. Any animals in poor health wereidentified for further monitoring and possible euthanasia. Body WeightsFor each dose, bodyweights were measured and recorded on the day ofdosing or the day prior to dosing. Detailed A detailed clinicalexamination for each animal Observations were performed pretest and atapproximately 1- 2 hours postdose. In addition, any positive clinicalsigns were recorded if observed.

FIG. 5 depicts pK data of Compound 1 capsule and tablets in a dog.

6.7. Clinical Protocol: A Two-Part, Phase 1 Study to Evaluate thePharmacokinetics and Pharmacodynamics of Multiple Dose Compound 1 andthe Effects of Food and Formulation on the Pharmacokinetics of SingleDose Compound 1 in Healthy Subjects

Primary Objectives:

Part 1: To evaluate the effect of multiple oral doses of Compound 1 onJNK activity following ultraviolet (UV) irradiation of human skin

Part 2: To evaluate pharmacokinetics of formulated Compound 1 tablets inthe presence of food, and the relative bioavailability of formulatedCompound 1 tablets compared to the active-ingredient-in capsule (AIC)formulation following a single oral dose.

Secondary Objectives:

Part 1: To evaluate the safety of single and multiple oral doses ofCompound 1.

Part 2: To evaluate the safety and tolerability of formulated Compound 1tablets when administered with food.

Study Design:

This is a two-part, Phase 1 study to evaluate the pharmacokinetics andpharmacodynamics of multiple doses of Compound 1 and the effects of foodand formulation on the pharmacokinetics of single dose Compound 1 inhealthy subjects.

Part 1:

This is an open-label, multiple-dose, 3-period, fixed sequence study, toevaluate the effect of Compound 1 on JNK activity following UVirradiation.

The study will consist of a screening phase (Day −21 to −2), minimumerythema dose (MED) determination prior to dosing, baseline (Day −1), 3treatment/assessment periods during which increasing doses of Compound 1are administered, and a follow-up visit. There will be no washout inbetween periods.

On the first day prior to dosing (baseline), and on the 6^(th) day ofeach dosing period (Days 6, 12, and 18), twice the MED intensity of UVlight will be administered to delineated sites on the subjects'buttocks. The irradiation at baseline (Day −1) should be administered atapproximately the same time that irradiation is scheduled on Days 6, 12,and 18, which is at 2 hours post dose. Eight hours after UV irradiation,a skin punch biopsy will be taken from the UV exposure site. The end ofconfinement will be Day 19. The follow-up visit will occur 7-10 days(i.e. Day 25 to Day 28) following the last dose in Period 3. An earlytermination (ET) visit will occur within 10 days of the day ofdiscontinuation.

The MED will be determined within 10 days of dosing in Period 1. It isrecommended that MED be done earlier than Day −2 in case MED isunsuccessful on the first attempt. Confinement is not required for MEDassessment.

Sixteen healthy qualified screened subjects with valid MEDs shouldreport to the study center on Day −1 of Period 1 for baselineassessments (including 2×MED irradiation with biopsy), and to beginconfinement.

Following scheduled check-in procedures, a skin test site will bedelineated on the subject's upper buttock between the beltline and thenatal cleft on right side. The test site will be minimum of 3 cm×3 cm,and will be outlined in ink (using a skin marker) with the subject lyingprone. Subjects will receive 2×MED UV irradiation to one site on thebuttock. One baseline skin punch biopsy will be taken from theUV-exposed site 8 hours (+/−10 minutes) after the UV-irradiation.

On Day 1, after a minimum 8 hours fast, subjects will receive the firstdose of study drug at approximately 8 AM:

All subjects will receive the following doses of Compound 1 in the fixedsequence below:

Treatment A: 60 mg Compound 1 as active in capsule (AIC), QD×6 days,followed by

Treatment B: 160 mg Compound 1 AIC, QD×6 days, followed by

Treatment C: 400 mg of Compound 1 AIC, QD×6 days.

During each period, subjects may be domiciled at the study site startingon Day −1 (or as early as Day 2, if Baseline 2×MED is scheduled early inthe day of Day −1), and will be discharged on Day 19 upon satisfactorysafety review and after the completion of study-related procedures.

The study drug (as AIC) will be given orally with approximately 240 mLof noncarbonated water (at room temperature). The first meal followingthe morning dose on the 6^(th) day of each dosing period will be 4 hourspost dose. On all other dosing days, the next meal/snack can be servedafter a minimum 2 hours fast after dosing.

On Baseline (Day −1), Days 6, 12, and 18, the skin test sites will bedelineated on the subject's upper buttock between the beltline and thenatal cleft on right side. The right side of the buttock will be dividedinto three (3) different test sites, one positioned site for 2×MEDirradiation at Baseline and at each of the 3 periods (Day 6, Day 12, andDay 18). Each test site will be as large as possible (minimum of 3 cm×3cm). The test site areas will be outlined in ink (using a skin marker)with the subject lying prone.

Subjects will receive 2×MED UV irradiation to one site on the buttock 2hours (+/−10 minutes) after administration of the study drug on Days 6,12, and 18. Ultraviolet irradiation at Baseline should be scheduledapproximately 2 hours after the planned dosing time for Day 1. It issuggested that the UV exposure sites be in sequential order startingwith the extreme left and moving across to the extreme right (i.e.exposure site 1 for Baseline; and exposure site 4 for Period 3).

One skin punch biopsy will be taken from the UV-exposed site 8 hours(+/−10 minutes) after the UV-irradiation. Four biopsies will be takenthroughout the study; ie. baseline and one biopsy per period. Thebiopsies will be processed into tissue slides by a third party to bedesignated by Celgene and analyzed by immunohistochemistry (ICH). Thisthird party will be blinded to the treatment periods (Baseline anddoses).

Subjects will be discharged from the clinical site on Day 19 after allscheduled procedures have been completed.

Adverse event (AE) monitoring, physical examinations, vital signs,electrocardiograms (ECGs), safety laboratory evaluation, and evaluationof wound healing will be performed at specified time points for safetyassessments.

Serial blood samples will be collected at pre-defined time points (Days6, 12, and 18: predose, 0.5, 2, 4, 6, 10, 12, and 24 hr postdose) foranalysis of Compound 1 levels. All evaluations will be performed inaccordance with the Table of Events and Procedures.

Procedures (except for the change in treatment) will be consistentacross all 3 periods.

Activities, environment, food, procedures, and schedule betweentreatment periods should be kept as consistent as possible.

Part 2:

Part 2 will be an open label, randomized, cross-over study with 3periods. The study will consist of a screening phase (Day −21 to −2),baseline (Day −1), 3 treatment/assessment periods, and a follow-up phonecall.

Twelve eligible subjects will check into the study center on Day −1 ofPeriod 1 for baseline assessments. On Day 1 of Period 1, subjects whocontinue to be qualified for participation in the study will be randomlyassigned to one of three dosing sequences during which they will receiveone of the following dosing regimens:

Treatment D: 2×100 mg Compound 1 as AIC, single oral dose administeredunder fasted conditions.

Treatment E: 1×200 mg Compound 1 (formulated tablet(s)) single oral doseadministered under fasted conditions.

Treatment F: 1×200 mg Compound 1 (formulated tablet(s)) single oral doseadministered under fed conditions (standard high fat breakfast).

TABLE 28 Food Effect Treatment Sequences Sequence Period 1 Period 2Period 3 Sequence 1 D E F Sequence 2 E F D Sequence 3 F D E

All subjects will fast overnight for at least 10 hours prior to dosing.Subjects receiving Treatment D and E (fasted) will continue to fast forat least 4 hours after dosing.

For Treatment F, subjects will receive a standard high fat(approximately 50% of the total caloric content of the meal),high-calorie (approximately 800 to 1000 calories) breakfast within 30minutes before dosing (based on FDA Center for Drug Evaluation andResearch Food Effect Guidance, (FDA, 2002)). The meal should deriveapproximately 150, 250, and 500 to 600 calories from protein,carbohydrates, and fat, respectively. Subjects must consume the entiremeal within 30 minutes of serving. Dosing must occur 30 minutes (+5minutes) after serving the meal.

During each study period, subjects will be housed at the study centerstarting on Day −1. Subjects will be discharged from the study center onDay 5 of the last period upon completion of study procedures. Eachtreatment period will be separated by a washout period of at least 7 butno more than 10 days from the last Compound 1 dose to the next scheduleddose. Serial blood samples will be collected during each period atpredose, 0.5, 1, 1.5, 2, 2.5, 3, 5, 8, 12, 24, 36, 48, 72, and 96 hourspost dose to determine the levels of Compound 1 in plasma.

If necessary, subjects may leave the clinic following scheduledprocedures on the morning of Day 5 of Periods 1 and/or 2, and return forthe following period. In certain instances, a longer washout may beacceptable if mutually agreed upon.

Study Population.

Healthy male and female subjects. Sixteen subjects will be enrolled inPart 1. Twelve volunteers will be enrolled in Part 2. Subjects may onlyparticipate in either Part 1 or Part 2.

Length of Study.

Part 1: approximately 7 weeks (including screening). Part 2:approximately 6 weeks (including screening).

The End of Trial is defined as either the date of the last visit of thelast subject to complete the study, or the date of receipt of the lastdata point from the last subject that is required for primary, secondaryand/or exploratory analysis, as pre-specified in the protocol and/or theStatistical Analysis Plan, whichever is the later date.

Study Treatments.

Compound 1 as AIC (30 mg and 100 mg dose strengths) and formulatedtablets (200 mg) will be supplied in bulk containers by Celgene.

Part 1: Treatment A (60 mg): 2×30 mg Compound 1 as AIC, QD×6 days;Treatment B (160 mg): 2×30 mg+1×100 mg Compound 1 as AIC, QD×6 days;Treatment C (400 mg): 4×100 mg Compound 1 as AIC, QD×6 days

Part 2: Treatment D: Compound 1 2×100 mg as AIC (200 mg), given QD inthe fasted state; Treatment E: Compound 1 as formulated tablets (1×200mg), given QD in the fasted state; Treatment F: Compound 1, asformulated tablets (1×200 mg), given QD in the fed state

Overview of Safety Assessments:

Safety will be monitored throughout the study. Safety evaluations willinclude adverse event (AE) reporting, PEs, vital signs, 12-lead ECGs,clinical laboratory safety tests (including liver function tests (LFTs),total cholesterol, triglycerides, high-density lipoprotein (HDL), andlow-density lipoprotein (LDL)) in addition to standard clinicalchemistry, hematology, and urinalysis tests), review of concomitantmedications/procedures, evaluation of wound healing, and pregnancy testsfor female subjects.

All AEs will be monitored and recorded throughout the study from thetime the informed consent form (ICF) is signed until study completion,and when made known to the Investigator within 28 days after the lastdose of Compound 1 (and those serious adverse events (SAEs) made knownto the Investigator at any time thereafter that are suspected of beingrelated to IP). All concomitant medications and procedures will bereviewed and recorded from the time the subject signs the ICF untilstudy completion. A follow-up visit (Part 1) or a follow-up phone call(Part 2) will be scheduled for all subjects. If a subject isdiscontinued from the study for any reason, an ET visit will beperformed.

Overview of Pharmacokinetic Assessments:

In both parts of the study, blood samples will be collected at specifiedtimes to determine plasma levels of Compound 1.

Part 1:

Collect blood/plasma on Day 6, 12, and 18: predose, 0.5, 2, 4, 6, 10,12, and 24 hour post dose;

Plasma PK parameters at steady state including but not limited to thefollowing: AUC_(τ) (Area under the plasma concentration-time curve fromtime zero to tau, where tau is the dosing interval); C_(max) (Maximumobserved plasma concentration), C_(min) (Minimum observed plasmaconcentration), T_(max) (Time to C_(max)).

Part 2:

Collect blood/plasma at each period: predose, 0.5, 1, 1.5, 2, 2.5, 3, 5,8, 12, 24, 36, 48, 72, and 96 hours post dose.

PK parameters at steady state including but limited to the following:AUC_(0-t), (Area under the plasma concentration-time curve from timezero to the last quantifiable concentration); AUC_(∞) (Area under theplasma concentration-time curve from time zero extrapolated toinfinity); CL/F (Apparent total plasma clearance when dosed orally);V_(z)/F (Apparent total volume of distribution when dosed orally, basedon the terminal phase); t_(1/2) (Terminal-phase elimination half-life);C_(max), (Maximum observed plasma concentration); and T_(max) (Time toC_(max)).

Overview of Pharmacodynamic Assessments:

Individual untraviolet B (UVB) exposure for MED determination:

UVB exposure within 10 days of first dosing in Period 1 consisting ofUVB exposure to 6 sites on the left buttock with incrementallyincreasing UV intensity

MED determination approximately 24 hours after UVB exposure

Individual UVB exposure (2×MED):

At Baseline (Day −1) and on Days 6, 12, and 18: 2×MED UVB exposure tosingle site on upper buttock at 2 hours post Compound 1 dose.

Collection of biopsies: One punch biopsy (approximately 3 mm in diameterby approximately 0.8 mm in depth) from each test site will be collectedat baseline (Day −1), and on Days 6, 12, and 18: eight (8) hours postUVB irradiation (a total of 4 punch biopsies).

Analysis of biopsy samples: Biopsies will be analyzed and phospho-cJunexpression will be analyzed by Immunohistochemistry (IHC) assays. Otherbiomarkers such as, but not limited to, c-Jun, may be explored using thesame skin biopsies and may be reported separately.

Phospho-cJun IHC data may be analyzed by either an analog scoring systemor by an automated measurement of integrated optical density by trainedindividuals who are blinded to the treatments. For Part 1 only thePhospho-c-Jun IHC data will be subjectively scored on a scale of 0 to 4based on the intensity and number of epidermal keratinocyte nucleistained within the tissue section by trained individuals blinded totreatment.

6.8. A Two-Part, Phase 1 Study to Evaluate the Pharmacokinetics andPharmacodynamics of Multiple Dose Compound 1 and the Effects of Food andFormulation on the Pharmacokinetics of Single Dose Compound 1 in HealthySubjects

Primary Objectives:

Part 1: To evaluate the effect of multiple oral doses of Compound 1 onJNK activity following ultraviolet (UV) irradiation of human skin; andPart 2: To evaluate the PK of formulated Compound 1 tablets in thepresence of food and the relative bioavailability of formulated Compound1 tablets compared to the active ingredient in capsule (AIC) formulationfollowing a single oral dose.

Secondary Objectives:

Part 1: To evaluate the safety of single and multiple oral doses ofCompound 1; and Part 2: To evaluate the safety and tolerability of theformulated Compound 1 tablets when administered with food.

Investigational Plan

Overall Study Design and Plan:

This was a two-part, two-site, Phase 1 study to evaluate the PK andpharmacodynamics (PD) of multiple doses of Compound 1 and the effects offood and formulation on the PK of a single dose of Compound 1 in healthysubjects. Part 1 and Part 2 of the study were conducted at two differentsites.

Part 1:

Part 1 was an open label, multiple dose, three period, fixed sequencestudy to evaluate the effect of Compound 1 on JNK activity following UVirradiation.

The study consisted of a screening phase (Days −21 to −2), minimumerythema dose (MED) determination prior to dosing, baseline (Day −1),three treatment/assessment periods during which increasing doses ofCompound 1 were administered, and a follow up visit. There was nowashout in between the dosing periods.

The MED was determined no later than Day −2 in case MED determinationwas unsuccessful on the first attempt. Confinement was not required forMED assessment. Sixteen healthy subjects with valid MEDs reported to thestudy center on Day −1 for baseline assessments (including 2×MEDirradiation with biopsy) and to begin confinement.

On Day 1, after a minimum of an 8-hour fast, subjects received the firstdose of Compound 1. All subjects received the following oral doses ofCompound 1 in the fixed sequence below:

-   -   Treatment A: 60 mg Compound 1 as AIC, QD×6 days;    -   Treatment B: 160 mg Compound 1 as AIC, QD×6 days; and    -   Treatment C: 400 mg Compound 1 as AIC, QD×6 days.

There was no washout between treatments. The end of confinement was Day19. The follow up visit occurred 7 to 10 days (i.e., Days 25 to 28)following the last dose in the third treatment period. An earlytermination (ET) visit occurred within 10 days of the day ofdiscontinuation.

Part 2:

Part 2 was an open label, randomized, crossover study with threeperiods. The study consisted of a screening phase (Days −21 to −2),baseline (Day −1), three treatment/assessment periods, and a follow upphone call.

Twelve eligible subjects reported to the study center on Day −1 ofPeriod 1 for confinement and baseline assessments. On Day 1 of Period 1,subjects who continued to be qualified for participation in the studywere randomly assigned to one of three dosing sequences (Table 29)during which they received one of the following dosing regimens:

-   -   Treatment D: 2×100 mg Compound 1 as AIC, single oral dose        administered under fasted conditions;    -   Treatment E: 1×200-mg Compound 1 formulated tablet, single oral        dose administered under fasted conditions; and    -   Treatment F: 1×200-mg Compound 1 formulated tablet, single oral        dose administered under fed conditions (standard high-fat        breakfast).

TABLE 29 Treatment Sequences-Part 2 Sequence Period 1 Period 2 Period 3Sequence 1 D E F Sequence 2 E F D Sequence 3 F D E

All subjects fasted overnight for at least 10 hours prior to dosing. ForTreatment F, subjects received a standard high-fat breakfast 30 minutesbefore dosing. Dosing occurred 30 minutes (±5 minutes) after serving themeal.

Each treatment period was separated by a washout period of 7 to 8 days.Subjects were discharged from the study center on Day 5 of the lastperiod upon completion of study procedures. An end-of-study (EOS) phonecall occurred 7 days following the last dose in the third period.

Discussion of the Study Design, Including Choice of Control Groups

Part 1:

This was a fixed sequence, multiple-treatment (from low to high doses)design to evaluate the effect of Compound 1 on JNK inhibition in humanskin. Three Compound 1 dose levels were explored to obtain an exposureresponse relationship. A fixed sequence allowed for efficient conduct ofthe trial. Although there was no washout between treatments, PD and PKcarry-over effects were not anticipated at Day 6 of each treatmentperiod when Compound 1 concentrations were expected to reach steadystate and PK and PD were assessed. The confounding factor of time withthe fixed sequence design was limited from both PK and PD perspectives.As such, this fixed sequence design allowed for adequate assessment ofthe study objectives.

The study was open label for the investigators, subjects, and sponsor;however, it was blinded for the third party processing and analyzing ofskin biopsy samples.

Each treatment was QD for 6 days. It was anticipated that the steadystate of exposure would be reached by Day 6.

Ultraviolet exposure occurred at baseline and at 2 hours postdose on Day6 of each treatment, which was the anticipated Compound 1 T_(max) atsteady state. The dose of UV was 2×MED UVB, which has been demonstratedto activate JNK. A skin biopsy was taken 8 hours post UV exposure, asthis is the time c Jun phosphorylation reaches plateau. A total of fourskin biopsies were taken, one at baseline and one each on the sixth dayof each treatment period.

The 2×MED UV exposure and skin biopsy procedures were well tolerated byhealthy subjects.

Part 2:

This was a randomized, single dose, three way crossover design toevaluate the relative bioavailability and food effect of Compound 1. Asingle 200-mg Compound 1 formulated tablet administered under fastedconditions (Treatment E) was assessed for bioavailability relative to2×100 mg Compound 1 as AIC (Treatment D). Food effect was explored bycomparing 200-mg Compound 1 formulated tablet administered under fastedconditions (Treatment E) to 200-mg Compound 1 formulated tabletadministered under fed conditions (Treatment F).

Selection of Study Population

Inclusion Criteria

Subjects must have satisfied all of the following criteria to beeligible for enrollment in the study:

1. Must have understood and voluntarily signed a written informedconsent document (ICD) prior to any study-related assessments/proceduresbeing performed.

2. Must have been able to communicate with the investigator and tounderstand and adhere to the study visit schedule and other protocolrequirements.

3. Must have been a male or female*, aged 18 to 65 years (inclusive) atthe time of signing the ICD.

* A woman of childbearing potential (WCBP) must have agreed to ongoingpregnancy testing during the course of the study and at the end of thestudy. This applied even if the subject practiced true abstinence fromheterosexual contact. A WCBP was a sexually mature woman who had notundergone a hysterectomy or who had not been naturally postmenopausalfor at least 24 consecutive months (i.e., who had had menses at any timein the preceding 24 consecutive months).

a. Females must have either committed to true abstinence** fromheterosexual contact (which must have been reviewed on a monthly basis)or agreed to use, and been able to comply with, two highly effectivecontraception methods without interruption 28 days prior to startingstudy drug, during the study therapy (including dose interruptions), andfor at least 28 days after discontinuation of study drug.

b. Females not of child-bearing potential should have been eithersurgically sterilized at least 6 months prior to screening (hysterectomyor bilateral tubal ligation) or been postmenopausal (defined as 24months with no menses prior to screening and with a plasmafollicle-stimulating hormone>40 IU/L at screening). Documentation wasrequired in cases of tubal ligation.

4. Males must have practiced true abstinence** or agreed to use a condom(a latex condom was recommended) during sexual contact with a pregnantfemale or WCBP while on study drug, or while participating in thisstudy, during dose interruptions, and for at least 28 days followingstudy drug discontinuation, even if he had undergone a successfulvasectomy.

** True abstinence was acceptable when this was in line with thepreferred and usual lifestyle of the subject (periodic abstinence (e.g.,calendar, ovulation, symptothermal, postovulation methods) andwithdrawal were not acceptable methods of contraception).

5. Must have had a body mass index (BMI=weight (kg)/(height (m)²)between 18 and 33 kg/m² (inclusive).

6. Must have been healthy as determined by the investigator based onmedical history, PE, clinical laboratory test results, vital signs, and12 lead ECGs.

a. Must have been afebrile (febrile was defined as ≥38° C. or 100.3°F.).

b. Must have had systolic blood pressure in the range of 80 to 140 mmHg,diastolic blood pressure in the range of 40 to 90 mmHg, and pulse ratein the range of 40 to 110 beats per minute.

c. Must have had QT interval corrected for heart rate using Fridericia'sformula value≤430 msec for male subjects and ≤450 msec for femalesubjects. An ECG could have been repeated up to three times to determinesubject eligibility.

7. Additional criteria for Part 1 only:

a. Must have been Fitzpatrick skin type I or II.

b. Must have had a valid MED obtained within 10 days prior to dosing.

Exclusion Criteria

The presence of any of the following excluded a subject from enrollmentin the study:

1. Had a history (i.e., within 3 years) of any clinically significantneurological, gastrointestinal, hepatic, renal, respiratory,cardiovascular, metabolic, endocrine, hematological, dermatological,psychological, or other major disorders.

2. Had any condition, including the presence of laboratoryabnormalities, that would have placed the subject at unacceptable riskif he/she were to have participated in the study or confounded theability to interpret data from the study.

3. Used any prescribed systemic or topical medication, includingvaccines, within 30 days of the first dose.

4. Used any nonprescribed systemic or topical medication (includingherbal medicines) within 14 days of the first dose administration (withthe exception of vitamin/mineral supplements).

5. Used any metabolic enzyme inhibitors or inducers (i.e., cytochromeP450 [CYP] 3A inducers and inhibitors or St. John's wort) within 30 daysof the first dose administration.

a. The University of Indiana “Cytochrome P450 Drug Interaction Table”was used to determine inhibitors and/or inducers of CYP3A4.

6. Had any surgical or medical conditions possibly affecting drugabsorption, distribution, metabolism, and excretion (e.g., bariatricprocedure).

a. Appendectomy and cholecystectomy were acceptable.

7. Donated blood or plasma within 8 weeks before the first doseadministration.

8. Had a history of drug abuse (as defined by the current version of theDiagnostic and Statistical Manual (DSM)) within 2 years before dosing orpositive drug screening test reflecting consumption of illicit drugs.

9. Had a history of alcohol abuse (as defined by the current version ofthe DSM) within 2 years before dosing or positive alcohol screen.

10. Known to have serum hepatitis, known to be a carrier of thehepatitis B surface antigen or hepatitis C antibody, or had a positiveresult to the test for human immunodeficiency virus antibodies atscreening.

11. Exposed to an investigational drug (new chemical entity) within 30days preceding the first dose administration or five half-lives of thatinvestigational drug, if known (whichever was longer).

12. Smoked more than 10 cigarettes per day or the equivalent in othertobacco products (self reported).

13. Had a history of multiple drug allergies (i.e., two or more).

Additional Exclusion Criteria for Subjects in Part 1 Only:

1. Were unable to evaluate the skin in and around the test sites due tosunburn, tans, uneven skin tones, tattoos, scars, excessive hair,numerous freckles, or any other disfiguration.

2. Used any creams or lotions (i.e., containing sun protection factor(SPF)) in the test area (i.e., buttocks) within 7 days of study start(Day 1).

3. Participated in any test for irritation or sensitization or any testinvolving UV exposures on the test area within 4 weeks of study start.

4. Participated in another study requiring biopsy (on the planned testarea) within the past 2 months.

5. Had a history of wound healing or blood clotting abnormality.

6. Had a history of keloid formation or hypertrophic scarring followingskin injury.

7. Had a history of severe reactions from exposure to sunlight.

8. Had a history of allergy to lidocaine or other similar localanesthetics.

9. Had a history of allergy to epinephrine.

Removal of Subjects from Therapy or Assessment

The following events were considered sufficient reasons fordiscontinuing a subject from the investigational product and/or from thestudy:

-   -   Adverse event;    -   Withdrawal by subject;    -   Death;    -   Lost to follow-up; and    -   Protocol violation.

The reason for discontinuation was recorded in the source documents andcase report form (CRF).

The decision to discontinue a subject remained the responsibility of thetreating physician, which was not delayed or refused by the sponsor.However, prior to discontinuing a subject, the investigator could havecontacted the medical monitor and forwarded appropriate supportingdocuments for review and discussion.

In the event that a subject was discontinued from the study for anyreason, an ET visit was performed. Every effort was made to ensure thatprocedures scheduled for the follow-up visit were performed at the ETvisit.

Treatments

Treatments Administered

Part 1:

All subjects received the following oral doses of Compound 1 as AIC:

-   -   Days 1 through 6: Treatment A: 60 mg Compound 1 AIC, QD×6 days;    -   Days 7 through 12: Treatment B: 160 mg Compound 1 AIC, QD×6        days; and    -   Days 13 through 18: Treatment C: 400 mg Compound 1 AIC, QD×6        days.

The treatments were administered in the morning following an overnightfast of at least 8 hours. All doses were administered with 240 mL ofnoncarbonated, room temperature water. Water was allowed as desiredexcept for 1 hour before and 1 hour after drug administration. The firstmeal following the morning dose on the sixth day of each dosing periodwas 4 hours postdose. On all other dosing days, the next meal/snack wasserved after a minimum 2 hours after dosing.

TABLE 30 Dosage Regimen-Part 1 Total Number Compound 1 Capsules ofCapsules per Treatment 30 mg 100 mg Dosing Day  60 mg Compound 1 2 0 2160 mg Compound 1 2 1 3 400 mg Compound 1 0 4 4

Subjects remained semi-recumbent for at least 2 hours postdose.

Part 2:

On Day 1 of each period, subjects were administered each treatment (D,E, or F):

-   -   Treatment D: 2×100 mg Compound 1 as AIC, single oral dose        administered under fasted conditions;    -   Treatment E: 1×200 mg Compound 1 (formulated tablet), single        oral dose administered under fasted conditions; and    -   Treatment F: 1×200 mg Compound 1 (formulated tablet), single        oral dose administered under fed conditions (standard high-fat        breakfast).

Treatments D and E were administered in the morning following anovernight fast of at least 10 hours. Subjects who received Treatments Dand E (fasted) continued to fast for at least 4 hours after dosing. ForTreatment F, subjects received a standard high fat (approximately 50% ofthe total caloric content of the meal), high calorie (approximately 800to 1000 calories) breakfast 30 minutes before dosing. The meal derivedapproximately 150, 250, and 500 to 600 calories from protein,carbohydrates, and fat, respectively. Subjects consumed the entire mealwithin 30 minutes of serving. Dosing occurred 30 minutes (±5 minutes)after serving the meal.

Subjects received two 100 mg Compound 1 as AIC or one 200-mg tabletdepending on the assigned treatment. All doses were administered with240 mL of noncarbonated, room temperature water. Water was allowed asdesired except for 1 hour before and 1 hour after drug administration.

Identity of Investigational Products

TABLE 31 Test Materials Information Compound 1 Compound 1 Compound 1Formulation AIC AIC Tablet Strength 30 mg 100 mg 200 mg

Method of Assigning Subjects to Treatment Groups

Prior to dosing, subjects were identified by their initials and uniquescreening number assigned by the clinical site. On the morning of Day 1,Period 1 and prior to dosing, each subject was assigned a unique subjectnumber.

For Part 2, subjects were randomly assigned to one of three treatmentsequences prior to dosing on the morning of Day 1, Period 1 according toa computer-generated randomization code.

Selection of Doses in the Study

Part 1:

Compound 1 doses were 60, 160, and 400 mg QD×6 days. Based uponavailable human PK and preclinical pharmacology data, the doses wereanticipated to provide a range of PD effects including both minimum andmaximum JNK inhibition. The dose range also covered the dose (240 mg QD)that yielded AUC comparable to the AUC (23400 ng·h/mL) in rats at whichanti fibrotic activity was observed.

In addition, Compound 1 doses selected were supported by toxicologystudies and human experience. Compound 1 has been tested in GLPrepeating dose toxicology studies in rats and dogs for 28 days. The AUCat the dog no observed adverse effect level was 81200 ng·h/mL. This washigher than the AUC observed in humans receiving 480 mg QD at steadystate, and Compound 1 doses up to 480 mg QD×14 days were well toleratedby healthy subjects.

Part 2:

The highest unit strength of the formulated tablet was 200 mgCompound 1. Tablets with other unit strengths are of the sameformulation. The available strengths for the AIC were 10, 30, and 100mg. Therefore, the bioavailability of a single 200 mg tablet (TreatmentE) was tested in comparison to 2×100 mg AIC reference (Treatment D).

The formulated tablets were planned to be used in future clinicaltrials; therefore, the food effect evaluated the PK of 200-mg Compound 1formulated tablet administered under fasted conditions (Treatment E) incomparison to 200-mg Compound 1 formulated tablet administered under fedconditions (Treatment F).

Pharmacokinetic, Pharmacodynamic, and Safety Variables

Pharmacokinetic Parameters

Method and Timing of Pharmacokinetic Sample Collection

Part 1:

Blood samples for Compound 1 plasma PK analysis were collected at thefollowing time points on Days 6, 12, and 18: predose and 0.5, 2, 4, 6,10, 12, and 24 hours postdose.

Part 2:

Blood samples for Compound 1 plasma PK analysis were collected at thefollowing time points in all periods: predose and 0.5, 1, 1.5, 2, 2.5,3, 5, 8, 12, 24, 36, 48, 72, and 96 hours postdose.

During Treatment D (Compound 1 AIC, fasted), DBS specimens (by lancet tothe finger) were collected from subjects at each PK time point and wereused to measure concentrations of Compound 1 in whole blood.

Determination of Drug Concentration

Concentrations of Compound 1 in plasma were measured using a validatedliquid chromatography tandem mass spectrometry (LC-MS/MS) assay. In Part2, concentrations of Compound 1 in whole blood were measured using avalidated LC-MS/MS method.

Calculation of Pharmacokinetic Parameters

Plasma and whole blood PK parameters were derived for Compound 1 bynoncompartmental analysis. Actual sampling times were used in thecalculation of PK parameters.

Part 1:

AUC_(τ): AUC from time zero to tau, where tau is the dosing interval.

C_(max): Maximum observed plasma concentration.

C_(min): Minimum observed plasma concentration.

T_(max): Time to C_(max).

Part 2:

AUC_(t): AUC from time zero to the last quantifiable concentration.

AUC_(∞): AUC from time zero extrapolated to infinity.

C_(max): Maximum observed plasma concentration.

T_(max): Time to C_(max).

CL/F: Apparent total plasma clearance when dosed orally.

V_(z)/F: Apparent total volume of distribution when dosed orally.

t_(1/2): Terminal phase elimination half-life.

Pharmacodynamic Parameters

Method and Timing of Pharmacodynamic Sample Collection

For Part 1, no later than 2 days prior to enrollment in Period 1 (i.e.,Day −2), six unprotected sites on the left buttock were exposed to UVBin incrementally increasing UV intensity, and the MED was determinedapproximately 24 hours (±1 hour) after UVB exposure.

On baseline (Day −1) and on the sixth day of each dosing period (Days 6,12, and 18), the skin test sites were delineated on the subject's upperbuttock between the beltline and the natal cleft on the right side. Theright side of the buttock was divided into four different test sites,one site for 2×MED irradiation at baseline and each of the three dosingperiods. Each test site was a minimum of 3 cm×3 cm. Subjects received2×MED UV irradiation at baseline (Day −1) at approximately the same timethat irradiation was scheduled on Days 6, 12, and 18, which was 2 hourspostdose. Eight hours after UV irradiation (±10 minutes), a skin punchbiopsy was taken from the UV exposure site. The biopsies were processedinto tissue slides by a third party and analyzed by immunohistochemistry(IHC). This third party was blinded to the treatment periods (baselineand doses).

Determination of Pharmacodynamic Parameters

Phospho-c-Jun expression in biopsies was analyzed by IHC. Phospho-c-JunIHC data were subjectively scored on a scale of 0 to 4 based on theintensity and number of epidermal keratinocyte nuclei stained within thetissue section by trained individuals blinded to treatment. The IHC wasalso analyzed by automated measurement of integrated optical density.

Study Subjects

Disposition of Subjects

Overall, 28 subjects were enrolled in this study and 27 subjectscompleted the study. In Part 1, 15 of 16 subjects completed the study.All 12 subjects enrolled and randomized in Part 2 completed the study.In Part 1, one subject experienced a treatment-emergent adverse event(TEAE) of viral infection that was assessed by the Investigator as notsuspected to be related to Compound 1. The viral infection began on Day10 and resulted in discontinuation of study procedures on Day 11. Thesubject remained at the site for monitoring until he was discharged onDay 13 at his request. A summary of subject disposition is presented inTable 32.

TABLE 32 Subject Disposition and Analysis Populations Part 1 Part 2Total Number of Subjects Enrolled (N) 16 12 28 Number of SubjectsCompleted (N (%)) 15 (93.8) 12 (100) 27 (96.4) Number of SubjectsDiscontinued (N (%)) 1 (6.3) — 1 (3.6) Number of Subjects in SafetyPopulation 16 (100) 12 (100) 28 (100) (N (%)) Number of Subjects in 16(100) 12 (100) 28 (100) PK Population (N (%)) Number of Subjects in 15(93.8) — 15 (53.6) PD Population (N (%)) Primary Reason forDiscontinuation from the Study Adverse Event 1 (100) — 1 (100) N = totalnumber of subjects; PD = pharmacodynamic; P = pharmacokinetic. Note:Percentages for the reasons for discontinuation are based on the numberof subjects who prematurely withdrew from the study. All otherpercentages are based on the number of subjects enrolled.

Pharmacokinetic/Pharmacodynamic Evaluation

Analysis Population

Pharmacokinetic Population:

The PK population included all 28 subjects (16 in Part 1 and 12 in Part2) in this study who were administered at least one dose of Compound 1.One subject in Part 1 was discontinued from study procedures on Day 11.Therefore, the PK samples were not collected on Days 12 or 18 for thissubject.

Pharmacodynamic Population:

The PD population included 15 of the 16 subjects in Part 1 of this studywho received all required doses of Compound 1 within a given period,were exposed to 2×MED, and had evaluable biopsies for at least onetreatment period (excluding the baseline biopsy). One subject wasexcluded from the PD population because his baseline phospho-c-Junoptical density score was more than four standard deviations (SDs) lowerthan the mean of the other subjects' baseline scores. Another subjectwas discontinued from the study on Day 11 and therefore has no evaluablebiopsies for Days 12 or 18. He was included in the PD population becausehe had biopsy data from Day 6.

Pharmacokinetic/Pharmacodynamic Results

Pharmacokinetic Results

Plasma and Whole Blood Concentrations for Compound 1

Mean (±SD) plasma concentrations versus time profiles for Compound 1(Part 1 and Part 2) are displayed in FIG. 103, FIG. 104 and FIG. 105,respectively.

Review of the individual concentration-time data indicated that vastmajority of the subjects at all dose levels showed quantifiable Compound1 plasma concentrations up to 96 hours post-dose. Plasma concentrationswere highly correlated with whole blood concentration for Compound 1 asshown in FIG. 106.

Summary statistics of plasma pharmacokinetic parameters for Part 1 andPart 2 are presented in Table 33 and Table 34, respectively.

Part 1:

Compound 1 was rapidly absorbed following single or multiple oral dosesat the dose levels evaluated with a median T_(max) of approximately 1.0to 4 hours postdose. After achieving C_(max), Compound 1 started todecline from plasma in a bi-exponential manner. The mean terminal halflife of Compound 1 was estimated to be between approximately 14 and 21hours following multiple doses. The systemic exposure of Compound 1(AUC_(∞), AUC_(t), and C_(max)) appeared to increase in a more thandose-proportional manner as the dose increased from 60 mg to 400 mgfollowing multiple oral doses.

TABLE 33 Summary of Pharmacokinetic Parameters of Compound 1 FollowingMultiple Oral Doses of 60, 160, and 400 mg (QD × 6 days), Part 1Geometric Mean (Geometric CV%) Treatment (Dose) A (60 mg) B (160 mg) C(400 mg) Parameter (N = 15) (N = 15) (N = 15) C_(max) 419 (24.7) 1460(25.1) 4460 (19.5) (ng/mL) C_(min) 22 (44.6) 65 (67.5) 212 (69.7)(ng/mL) T_(max) ^(a)) 1.95 (1.92, 4.00) 1.95 (1.92, 2.00) 1.97 (1.92,5.93) (hr) AUC_(0-τ) 2290 (24.6) 8560 (32.6) 31300 (31.4) (ng · h/mL)AUC_(0-τ) = area under the plasma concentration versus time curve fromtime 0 to τ (tau), where τ is 24 hours (the length of the dosinginterval); C_(max) = maximum observed plasma concentration; C_(min) =observed plasma concentration at 24 hours postdose; CV = coefficient ofvariation; N = total number of subjects; T_(max) = time to maximumobserved plasma concentration. ^(a))T_(max) is presented as median(minimum, maximum).

Treatment A: 60 mg Compound 1 as AIC, QD×6 days.

Treatment B: 160 mg Compound 1 as AIC, QD×6 days.

Treatment C: 400 mg Compound 1 as AIC, QD×6 days.

TABLE 34 Summary of Pharmacokinetic Parameters of Compund 1 Following aSingle Oral Dose of 2 × 100 mg capsules or a 200 mg Tablet under Fed orFasted Conditions, Part 2 Geometric Mean (Geometric CV %) Treatment(Dose) D (200 mg) E (200 mg) F (200 mg) Parameter (N = 12) (N = 12) (N =12) AUC_(τ) 12900 (21.3) 11900 (32.2) 12000 (27.4) (ng · h/mL) AUC_(∞)13100 (21.7) 12200 (32.5) 12300 (27.00) (ng · h/mL) C_(max) 2080 (17.5)1730 (70.7) 1840 (33.1) (ng/mL) T_(max) ^(a)) 2 (1.00, 3.00) 2 (1.50,3.00) 3.00 (1.50, 5.00) (hr) t_(1/2) 20.3 (28.9) 20.1 (21.5) 21.7 (29.7)(hr) CL/F 15.2 (21.7) 16.4 (32.5) 16.3 (27.0) (mL/min) Vz/F 447 (33.4)477 (30.5) 510 (35.5) (L) AUC_(∞) = area under the plasma concentrationversus time curve from time zero to infinity; AUC_(τ) = area under theplasma concentration versus time curve from time 0 to the lastquantifiable concentration; C_(max) = maximum observed plasmaconcentration; CL/F = apparent total plasma clearance; N = total numberof subjects; t_(1/2) = terminal elimination half-life; T_(max) = time tomaximum observed plasma concentration; Vz/F = apparent total volume ofdistribution. ^(a))T_(max) is presented as median (minimum, maximum).

Treatment D: 2×100 mg Compound 1 as AIC, single oral dose administeredunder fasted conditions.

Treatment E: 1×200 mg Compound 1 as formulated tablet(s), single oraldose administered under fasted conditions.

Treatment F: 1×200 mg Compound 1 as formulated tablet(s), single oraldose administered under fed conditions.

In Part 2, Compound 1 was administered as a single oral dose of 2×100 mgcapsules or 200 mg tablet. Under fasted conditions, the tablet achievedan equivalent AUC_(t) and AUC, compared to the capsules, but a lowerC_(max) (˜17%) relative to the capsule formulation (Table 34). T_(max)was similar following either formulation.

As shown in Table 33 and Table 35, Compound 1 administered as a singleoral dose of 200 mg tablet under fasted or fed conditions resulted inequivalent AUC_(t) and AUC_(∞) with a slightly higher C_(max) (by ˜6%)in the fed state compared to the fasted state. The median T_(max) ofCompound 1 was delayed by 0.87 hours after administration of a single200 mg Compound 1 tablet under fed conditions compared with fastedconditions (Table 36).

Statistical Analysis of Pharmacokinetic Parameters

As shown in Table 35, the 90% CIs of the geometric mean ratios betweentreatments for AUC_(t) and AUC_(∞) were fully contained within the rangeof 80% to 125%, but the 90% CIs of the geometric mean ratios betweentreatments for C_(max) were outside of the range of 80% to 125%. Thestatistical analysis further supports that the 200 mg tablet providesequivalent extent of exposure though the peak concentration (C_(max)) is˜17% lower. The results also demonstrate that the presence of food hasno effect on the PK of the tablet formulation of Compound 1.

When Compound 1 was administered as a 200 mg tablet or 2×100 mgcapsules, there was no statistically significant change (p>0.05) noted.

When Compound 1 was administered as a tablet with food, a statisticallysignificant (p<0.05) increase (by 0.87 hours) in the median t_(max) wasobserved when compared with fasted conditions (90% CI of mediandifference does not contain zero), but this change (a 0.87 hour-delay inabsorption) is considered not clinically meaningful.

TABLE 35 Statistical Analysis of Plasma Pharmacokinetic Parameters ofCompound 1 (Pharmacokinetic Population) 90% CI of Ratio (%) of Ratio ofIntra- Geometric Geometric Geometric subject Parameter Treatment N MeanComparison Means Means CV % AUC_(t) D 12 12889 E/D 92.6 (82.7, 16.1 (ng· hr/mL) 103.6) E 12 11933 F/E 100.6 (89.8, 112.6) F 12 12002 AUC_(∞) D12 13123 E/D 92.9 (82.9, 16.2 (ng · hr/mL) 104.0) E 12 12187 F/E 100.8(90.0, 112.9) F 12 12285 C_(max) D 12 2082 E/D 82.9 (64.3, 37.2 (ng/mL)106.8) E 12 1726 F/E 106.4 (82.6, 137.1) F 12 1836 AUC_(0-∞) = areaunder the plasma concentration-time curve from time 0 extrapolated toinfinity; AUC_(0-t) = AUC from time 0 to time t where t is the lastmeasurable time point; C_(max) = maximum observed plasma concentration;LS = least squares.

Treatment D: 2×100 mg Compound 1 as AIC, single oral dose administeredunder fasted conditions.

Treatment E: 1×200 mg Compound 1 as formulated tablet(s), single oraldose administered under fasted conditions

Treatment F: 1×200 mg Compound 1 as formulated tablet(s), single oraldose administered under fed conditions.

Geometric least squares (LS) means, ratio (fed/fasted) and 90%confidence intervals (CIs) of the ratio of geometric LS means were froman analysis of variance (ANOVA) model with treatment, period, andsequence as fixed effects, and subject nested within sequence as arandom effect on the natural log-transformed pharmacokinetics.

The ratio and 90% CI of the ratio were presented as a percentage.

Intrasubject coefficient of variation=square root of (exp(mean squareerror of ANOVA)−1)×100.

TABLE 36 Statistical Analysis of T_(max) (Pharmacokinetic Population)90% Confidence Interval of Median Median Parameter Treatment N MedianComparison Difference Difference P-Value t_(max) (hr) D 12 2.00 E/D 0.01(0.00, 0.25) 0.3438 E 12 2.00 F/E 0.87 (0.25, 1.50) 0.0234 F 12 3.00t_(max) = time to maximum observed plasma concentration.

Treatment D: 2×100 mg Compound 1 as AIC, single oral dose administeredunder fasted conditions.

Treatment E: 1×200 mg Compound 1 as formulated tablet(s), single oraldose administered under fasted conditions

Treatment F: 1×200 mg Compound 1 as formulated tablet(s), single oraldose administered under fed conditions.

The median, median difference (fed-fasted), and 90% confidence intervalof the median difference were from the Hodges-Lehmann estimate.

The p-value was from the Wilcoxon signed-rank test.

Pharmacodynamic Results

Phospho c-Jun Immunohistochemistry: Quantitative Analysis

Phospho c-Jun IHC images were analyzed at Quintiles for integratedoptical density of positive nuclear staining using Aperio imagingsoftware (Leica Biosystems). The Phospho c-jun score (Optical DensityScale) reflects the percentage of nuclei with ‘3+’ staining intensity(the cutoff for determining positive staining) as determined by theAperio nuclear phospho c-jun quantitative image analysis algorithm. Thepercent of baseline of the individual integrated optical density bytreatment is presented in FIG. 107. While the phospho c-jun staining isnot decreased from baseline in the 60 mg dose group, there is a 7.5%decrease in the 160 mg dose group (p=0.18), and a 29.5% decrease in the400 mg group (p<0.0001).

The following are the percentages of subjects with a decrease in opticaldensity score compared to baseline values:

60 mg dose: 4/14=29%

160 mg dose: 11/13=85%

400 mg dose: 13/13=100%

Phospho c-Jun Immunohistochemistry: Histopathology Scores

Phospho c-Jun immunohistochemistry (IHC) images were scored by 2independent pathologists from Quintiles using a scoring scale of 0-4.The percentage of epithelial c-Jun positive nuclei was scored asfollows:

0=0% to 19%

1=20% to 39%

2=40% to 59%

3=60% to 79%

4=80% to 100%.

The individual median histopathology scores by treatment are presentedin FIG. 107, and the absolute change from baseline is presented in FIG.108. The change from baseline in median histopathology scores is notsignificantly affected by treatment. There are nominally more decreasesin score (18), than increases (14), across all three treatment groups,and the percentage of individuals showing either no change or a decreasein score increases in a dose-dependent manner: 8/15=53% in the 60 mgdose group; 10/14=71% in the 160 mg dose group, and 11/14=79% in the 400mg dose group.

Pharmacokinetic and Pharmacodynamic Summary and Conclusions

Pharmacokinetic Summary and Conclusions

The PK of Compound 1 was well characterized in healthy subjectsfollowing administration of a single oral dose of 200 mg under fasted orfed conditions and multiple oral doses of Compound 1 at 60 mg, 160 mgand 400 mg QD.

The systemic exposure of Compound 1 (AUC_(t) and C_(max)) appeared toincrease in a more than dose-proportional manner as the dose wasincreased from 60 mg to 400 mg following multiple doses.

Compound 1 was rapidly absorbed and slowly eliminated from plasma with aterminal elimination t_(1/2) of approximately 20 hours following asingle oral dose of 200 mg.

Under fasted conditions, the 200 mg tablet administration resulted in anequivalent AUC_(t) and AUC_(∞) compared to the 2×100 mg capsuleadministration, but a lower C_(max) (˜17%) relative to the capsuleformulation.

Food had no effect on the PK of a single oral 200 mg tablet of Compound1 in healthy subjects.

Compound 1 plasma concentrations correlated well with whole bloodconcentrations.

Pharmacodynamic Summary and Conclusions

Compound 1 inhibited UVB-induced phospho c-jun expression in skin in adose-dependent manner. At the highest tested Compound 1 dose of 400 mgthe decrease in UVB-induced phospho c-jun was 29.5%, at the intermediate160 mg dose—7.5%, and there was no change at the lowest 60 mg dose(measured by automated quantitative image analysis of integrated opticaldensity).

The Compound 1-associated inhibition of UVB-induced phospho c-junexpression in skin did not reach significance using the histopathologistscoring system. This may be due to the limitations of the assay, whichutilizes subjective scoring of the intensity and number of stainedepidermal keratinocyte nuclei by trained individuals (on a scale of 0 to4).

Safety Summary and Conclusions

Overall, 11 of 28 subjects (39.3%) reported 17 TEAEs.

No subjects experienced an SAE or severe TEAE. The majority of the TEAEswere mild in severity. One subject discontinued from the study due to aTEAE of viral infection that was judged by the investigator as notsuspected of being related to Compound 1. Overall in this study, 11 of28 subjects (39.3%) reported 17 TEAEs. The most common TEAEs on thestudy were gastrointestinal in nature and included nausea (observed in 4subjects) and diarrhea (observed in 2 subjects) that were judged by theinvestigator as suspected of being related to Compound 1. No clinicallysignificant changes or findings were noted in clinical laboratoryevaluations, vital sign measurements, or ECGs. Overall, there were noremarkable clinical safety findings during the study as nausea anddiarrhea were previously reported in Compound 1 SAD/MAD study and aremanageable with standard of care.

Multiple doses of Compound 1 were safe and well tolerated whenadministered as 60, 160, and 400 mg AIC QD for 6 days in healthy malesubjects. Single doses of 200 mg as formulated tablets in both fed andfasted states and AIC in the fasted state were safe and well toleratedin healthy subjects.

DISCUSSION AND OVERALL CONCLUSIONS Discussion

The primary objectives of the study were:

to evaluate the effect of multiple oral doses of Compound 1 on JNKactivity following UV irradiation of human skin;

to evaluate the PK of formulated Compound 1 tablets in the presence offood; and

to evaluate the relative bioavailability of formulated Compound 1tablets compared to the AIC formulation following a single oral dose.

Secondary objective was to evaluate the safety and tolerability ofsingle and multiple oral doses of Compound 1 and formulated Compound 1tablets when administered with food.

In Part 1, Compound 1 was administered as multiple oral doses of 60 mg,160 mg, and 400 mg QD for 6 days to determine steady-state exposure ofCompound 1. Steady state exposure of Compound 1 (AUC_(t), and C_(max))appeared to increase in a more than dose-proportional manner as the dosewas increased from 60 mg to 400 mg following multiple doses. Based onthe coefficient of variance, inter-subject variability for the PKparameters was generally in a moderate range.

In Part 2, Compound 1 was administered as a single oral dose of 200 mgcapsule or 200 mg tablet under fasted and fed conditions to determinewhether or not the 200 mg tablet achieves a comparable exposure to the200 mg capsule and whether or not food affects the PK of Compound 1.

The PK of Compound 1 was characterized by rapid absorption with a medianT_(max) of approximately between 1.95 to 3 hours postdose for all doses.After achieving C_(max), Compound 1 started to decline from plasma in abi-exponential manner. The mean terminal elimination half-life ofCompound 1 was estimated to be approximately 20 hours.

Under fasted conditions, a single 200 mg tablet administration achievedan equivalent AUC_(t) and AUC_(∞) to the 2×100 mg capsuleadministration, but a lower C_(max) (˜17%) relative to the capsuleformulation. T_(max) was similar following dosing with eitherformulation. The results demonstrate that the 200 mg tablet isequivalent in extent of exposure with ˜17% lower peak exposure; thislowering of peak exposure if expected as food often extends the time toT_(max).

Compound 1 administered as a single oral dose of 200 mg tablet underfasted or fed conditions resulted in equivalent AUC_(t) and AUC_(∞) witha slightly higher C_(max) (by ˜6%) in the fed state compared to thefasted state. The median tmax of Compound 1 was delayed by 0.87 hoursafter administration of a single 200 mg Compound 1 tablet under fedconditions compared with fasted conditions. As a result of the smalldifferences in C_(max) and no change in AUC exposure, food is notconsidered to meaningfully affect the PK of Compound 1.

Compound 1 inhibited UVB-induced phospho c-jun in the skin in adose-dependent manner as measured by quantitative image analysis ofphospho c-jun IHC optical density. The percentage of subjects with adecrease from baseline in optical density score increased from 29% inthe 60 mg dose group to 85% in the 160 mg dose group and 100% in the 400mg dose group. Measured as percent change from baseline in opticaldensity score, Compound 1 significantly decreased UVB-induced phosphoc-jun by 29.5% in the skin at a dose of 400 mg, with a non-significantdecrease of 7.5% at a dose of 160 mg.

Compound 1 was safe and well tolerated when administered to healthysubjects as multiple oral doses of 60, 160, or 400 mg AIC QD for 6 days.A single oral dose of 200 mg Compound 1 was safe and well tolerated whenadministered to healthy subjects in the fasted state as AIC or aformulated tablet and in the fed state as a formulated tablet.

No subjects experienced an SAE or severe TEAE. The majority of the TEAEswere mild in severity. One subject discontinued from the study due to aTEAE of viral infection that was judged by the investigator as notsuspected of being related to Compound 1. Overall in this study, 11 of28 subjects (39.3%) reported 17 TEAEs. The most common TEAEs on thestudy were gastrointestinal in nature and included nausea (observed in 4subjects) and diarrhea (observed in 2 subjects) that were judged by theinvestigator as suspected of being related to Compound 1. No clinicallysignificant changes or findings were noted in clinical laboratoryevaluations, vital sign measurements, or ECGs.

Conclusions

Pharmacokinetic Conclusions

The systemic exposure of Compound 1 (AUC_(t) and C_(max)) appeared toincrease in a more than dose-proportional manner as the dose wasincreased from 60 mg to 400 mg following multiple doses.

Under fasted conditions, 200 mg tablet administration resulted in anequivalent AUC_(t) and AUC_(∞) to the 200 mg capsule administrationthough a lower C_(max) (˜17%) was noted.

Food had no effect on the PK of a single oral 200 mg tablet of Compound1 in healthy subjects.

Compound 1 plasma concentrations correlated well with Compound 1 wholeblood concentrations.

Pharmacodynamic Conclusions

Compound 1 inhibited UVB-induced phospho c-jun expression in skin in adose-dependent manner. At the highest tested Compound 1 dose of 400 mgthe decrease in UVB-induced phospho c-jun was 29.5%, at the intermediate160 mg dose—7.5%, and there was no change at the lowest 60 mg dose(measured by automated quantitative image analysis of integrated opticaldensity).

The Compound 1-associated inhibition of UVB-induced phospho c-junexpression in skin did not reach significance using the histopathologistscoring system. This may be due to the limitations of the assay, whichutilizes subjective scoring of the intensity and number of stainedepidermal keratinocyte nuclei by trained individuals (on a scale of 0 to4).

Safety Conclusions

Compound 1 was safe and well tolerated in healthy male subjects whenadministered as multiple oral doses of 60, 160, and 400 mg AIC QD for 6days.

A single oral dose of 200 mg Compound 1 was safe and well tolerated inhealthy subjects when administered in the fasted state as AIC or aformulated tablet and in the fed state as a formulated tablet.

6.9. A Phase 1B, Multicenter, Open-Label, Staggered-Dose Study to Assessthe Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics ofMultiple Doses of Compound 1 for 12 Weeks in Subjects with PulmonaryFibrosis

Primary Objectives:

To evaluate the safety and tolerability of Compound 1 in subjects withpulmonary fibrosis.

Secondary Objectives:

To evaluate the pharmacokinetic (PK) profile of Compound 1 from plasmasamples in subjects with pulmonary fibrosis.

Study Design.

This is an open-label, staggered dose-escalation, cohort expansion studythat will enroll subjects at multiple study sites in the United Statesof America (USA) and Australia. The study will consist of two treatmentarms:

-   -   Low dose (100 mg) Compound 1 administered orally once daily (QD)        for 12 continuous weeks.    -   High dose (200 mg) Compound 1 administered orally QD for 12        continuous weeks.

The high dose Compound 1 arm will not start until at least threesubjects complete a minimum of 2 weeks of low dose Compound 1 and thelow dose treatment arm is determined not to meet the study doseescalation stopping criteria.

Each subject will participate in a Screening Period (up to 4 weeks priorto treatment), a 12-week Treatment Phase, and a 4-week Follow-up visit.Subjects will be screened for eligibility. Subjects who meet all of theinclusion criteria and none of the exclusion criteria at Screening willreturn to the study site on Day 1 for assessments and to beginadministration of a QD dose of Compound 1, according to the dose levelin which the subject is enrolled. Three subjects will initially beenrolled to receive low dose Compound 1, 100 mg QD, and will beevaluated for all scheduled assessments through 2 weeks of treatment.Once a total of three subjects have completed the Week 2 visit, adecision to continue the study at the high dose level (200 mg QD) willbe determined.

If the criteria for escalation to the high dose are met, the low dose(100 mg QD) subjects will remain on low dose and three additionalsubjects will be enrolled at the high dose level (200 mg QD). Apredefined dose-escalation decision tree will be utilized to determinethe subsequent treatment arm if criteria for escalation to the high doseis not met. If one of the three subjects at the low dose (100 mg QD)experiences an event that meets the individual subject dose stoppingcriteria, another three subjects will be enrolled in the low dose arm.Dose escalation will not occur if two or more of the three subjects meetthe individual subject dose stopping criteria. All subjects (low andhigh dose) will remain on Compound 1 for a total of 12 weeks unless anindividual subject experiences an event that meets any of the individualsubject stopping criteria. In addition, the dose of Compound 1 may bereduced to the low dose level (100 mg QD) for any individual subject atthe high dose level (200 mg QD) who meets any of the individual subjectdose reduction criteria. If two or more subjects in the high dose armexperience an event that meets the individual stopping criteria, the 200mg QD dose arm may be repeated in three additional subjects, or threeadditional subjects will be enrolled in the high dose level, or thestudy may be stopped.

Study visits will occur at Screening, Day 1, and Weeks 1, 2, 3, 4, 6, 8,10, 12, and 16. Blood and urine samples will be collected at specifiedtimes for clinical safety laboratory assessments, PK assessments, and PDanalyses. Safety will be monitored throughout the study.

In the event that a subject discontinues from the study, an earlytermination visit will be performed.

Study Population.

The study population will consist of approximately nine to 18 adult maleor female subjects at least 18 years of age with pulmonary fibrosis.Specifically, subjects will have a documented usual interstitialpneumonia (UIP) pattern or nonspecific interstitial pneumonia (NSIP)pattern based on computed tomography OR a documented fibrotic NSIP ordocumented UIP pattern on surgical lung biopsy. The underlying diseasemay include, but is not limited to, connective tissue disease-associatedinterstitial lung disease, interstitial pulmonary fibrosis, idiopathicpulmonary fibrosis (IPF), environmental- or chemical-related pulmonaryfibrosis, or Hermansky-Pudlak syndrome.

Length of Study.

The study duration for each subject will be up to 20 weeks and includesa 4-week Screening period, a 12-week Treatment Phase, and a 4-weekFollow-up. The total duration of the study, from first subject's firstvisit to last subject's last visit, is expected to be approximately 12months.

End of Study.

The end of study is defined as either the date of the last visit of thelast subject to complete the study, or the date of receipt of the lastdata point from the last subject that is required for primary,secondary, and/or exploratory analysis, as prespecified in the protocolor the statistical analysis plan, whichever is the later date.

Study Treatments.

Study treatment arms include:

-   -   Low dose (100 mg) Compound 1, administered orally QD for 12        weeks.    -   High dose (200 mg) Compound 1, administered orally QD for 12        weeks.

The high dose Compound 1 arm will start after at least three subjectscomplete a minimum of 2 weeks of low dose Compound 1 and the low dosetreatment arm is determined not to meet the study dose escalationstopping criteria.

Individual Subject Stopping Criteria.

Compound 1 dosing should be stopped for a subject if any of thefollowing individual subject stopping criteria occur:

-   -   Nausea, vomiting, or diarrhea that results in electrolyte        (sodium, chloride, potassium, and/or creatinine) abnormalities        and/or that requires intravenous hydration.    -   Intestinal intussusception, bowel obstruction, or        moderate/severe gastrointestinal bleed as determined by the        Investigator.    -   Any serious adverse event (SAE) considered by the Investigator        to be related to Compound 1.    -   Alanine aminotransferase (ALT) or aspartate aminotransferase        (AST)>8× upper limit of normal (ULN).    -   ALT or AST>5×ULN for more than 2 weeks.    -   ALT or AST>3×ULN and total bilirubin>2×ULN.    -   ALT or AST>3×ULN and with the appearance of fatigue, nausea,        vomiting, right upper quadrant pain or tenderness, fever, rash        and/or eosinophilia (>5%).    -   Any other event that is deemed to pose an unacceptable risk to        the subject.

Subjects who meet individual subject dose stopping criteria due to anaminotransferase AST or ALT or bilirubin elevation should not bere-challenged. Rechallenge for any event other than an AST, ALT, orbilirubin elevation may occur at the discretion of the Investigator.Subjects should be rechallenged at the same dose being administeredprior to meeting the individual subject stopping criterion. However, asubject in the high dose group may be dose-reduced to 100 mg should theInvestigator and Sponsor elect that it is in the best interest of thesubject.

Any subject experiencing an event meeting the individual subject dosestopping criteria which is considered by the Investigator to be relatedto Compound 1 administration will be accounted for during the doseescalation decision, even if that subject has not completed a total of 2weeks of dosing.

Individual Subject Dose Reduction Criteria.

The individual subject dose reduction criteria apply to subjectsreceiving high dose Compound 1 only. Since there is no dose reductionfor subjects receiving low dose Compound 1, low dose subjects meetingthese criteria should be closely monitored, considered for doseinterruption prior to rechallenge at 100 mg QD (at the discretion of theInvestigator), considered for dose discontinuation, or discontinued fromstudy when and if the event worsens to the point of meeting individualsubject stopping criteria.

In the event that a subject at the 200 mg QD dose experiences an eventthat meets the individual subject dose reduction criteria, the dose maybe reduced to 100 mg QD after the subject has recovered from the event.Subject dosing should be reduced if any one of the following individualsubject dose reduction criteria occur:

-   -   ALT or AST>3×ULN which is confirmed by repeat analysis AND does        not meet individual subject stopping criteria AND has no sign of        severe liver toxicity. The Investigator should also consider        discontinuing confounding medical products and monitoring the        subject closely.    -   Any subject experiencing moderate or severe gastrointestinal        adverse events (AEs) such as abdominal discomfort, nausea or        vomiting may be treated symptomatically (ondansetron, bismuth        subsalicylate, 5-HT₃, etc) at the discretion of the        Investigator. If the event is not improved after 5 days, the        dose will be held until the event is improved, at which time        Compound 1 will be resumed at the reduced dose.    -   Any other condition that is considered by the Investigator to be        related to Compound 1 and is considered by the Investigator to        improve with a dose reduction. The Investigator is to notify        Celgene in a timely manner of any such dose reductions.

Study Dose Escalation Stopping Criteria.

The criteria for stopping the escalation from the low dose treatment armof 100 mg to the high dose arm of 200 mg QD will be evaluated after atleast three subjects complete a minimum of 2 weeks of low doseCompound 1. The high dose (200 mg QD) Compound 1 arm will only beenrolled if the predefined dose escalation criteria are met.

Safety parameters reviewed prior to each dose escalation will includereview of relevant AEs, physical examination findings, vital signs, 12lead electrocardiograms, clinical laboratory safety tests, andconcomitant medications/procedures.

Overview of Pharmacokinetic Assessments.

Pharmacokinetic endpoints by

-   -   Compound 1 plasma sample concentrations sparsely collected    -   Compound 1 dry blood spot sample concentrations sparsely        collected

Population-based PK approach as appropriate for the following (but notlimited to) parameters:

-   -   Apparent clearance.    -   Apparent central volume of distribution.    -   First-order rate of absorption.    -   Disease as a covariate may be explored in the population PK        analysis. The derived PK parameters such as the maximum plasma        concentration of the drug and the area under the plasma        concentration-time curve may be also determined based on the        population PK model as appropriate.

Overview of Pharmacodynamic Assessments.

Blood draw for PD biomarkers may include but are not limited to:

-   -   Matrix metalloproteinase-7    -   Tenascin C

Overview of Efficacy Assessments. Exploratory efficacy assessmentsinclude:

-   -   Pulmonary function tests which, at a minimum, are to include        forced vital capacity, forced expiratory volume in 1 second, and        lung diffusion capacity.    -   Oxygen saturation by pulse oximetry.

Overview of Safety Assessments.

Safety will be monitored throughout the study. The safety of Compound 1will be evaluated based on the following assessments:

-   -   Complete physical examination.    -   Clinical laboratory assessments (chemistry, hematology,        urinalysis with microscopy).    -   Urine pregnancy tests.    -   miR-122 levels. Prompt reflex assessments of miR-122 levels will        be performed for clinical signs of liver toxicity or liver        function test abnormality (AST or ALT>2.5×ULN) or at        Investigator discretion.    -   Serology (hepatitis B surface antigen, hepatitis C virus        antibody, and human immunodeficiency virus)    -   Hepatic ultrasound.    -   INR.    -   Vital signs including heart rate, blood pressure, respiratory        rate, and temperature.    -   12-lead electrocardiogram.    -   Adverse Events. All AEs will be monitored and recorded        throughout the study from the time the informed consent form is        signed until 28 days after the last dose of Compound 1. Any SAEs        made known to the Investigator at any time thereafter that are        suspected of being related to Compound 1 administration must        also be reported.    -   Concomitant medications and procedures will be reviewed and        recorded from the time the subject signs the informed consent        form until the end of the study.

Prompt reflex assessments will be performed for clinical signs of livertoxicity or liver function test abnormality (AST or ALT>2.5×ULN) or atthe Investigator's discretion. Reflex assessments of liver toxicityinclude repeat clinical laboratory assessments, miR-122, a hepaticultrasound, a serology test for hepatitis B surface antigen, hepatitis Cvirus antibody, and human immunodeficiency virus, and an internationalnormalized ratio. Additional evaluations should be performed at theinvestigator's discretion based upon the subject's signs and symptoms.The Investigator should also consider discontinuing confounding medicalproducts and monitoring the subject closely.

Safety review meetings will occur:

-   -   Every 4 weeks subsequent to the first subject dosed.    -   After three subjects complete the initial 2 weeks of treatment        with low dose Compound 1.    -   In the event that a significant toxicity is observed in any        subject as determined by the Investigator.

Inclusion Criteria.

Potential subjects must satisfy all of the following criteria to beenrolled into the study: 1. Subject≥18 years of age; 2. Documentedclinical diagnosis of a fibrotic lung disease supported by at least oneof the following: a. Usual interstitial pneumonia (UIP) pattern based oncomputed tomography (CT scan); or b. Nonspecific interstitial pneumonia(NSIP) pattern based on CT scan; or c. A documented fibrotic NSIP onsurgical lung biopsy; or d. A documented UIP pattern on surgical lungbiopsy. The underlying etiology of the fibrotic lung disease may be ofany cause, including, but NOT LIMITED TO any of the following:Connective tissue disease-associated interstitial lung disease,idiopathic pulmonary fibrosis (IPF), environmental or chemical-relatedpulmonary fibrosis, other forms of interstitial pulmonary fibrosis,Hermansky-Pudlak syndrome; 3. Must understand and voluntarily sign awritten ICF prior to any study-related procedures being performed; 4.Must be able to communicate with the Investigator, understand and complywith the requirements of the study, and agree to adhere to restrictionsand examination schedules; 5. AST or serum glutamic-oxaloacetictransaminase within limits of normal; 6. ALT or serum glutamic pyruvictransaminase within limits of normal; 7. Total bilirubin and INR withinlimits of normal; 8. No clinically significant laboratory test resultsas determined by the Investigator; 9. Male subjects agree to use barriercontraception NOT made of natural (animal) membrane (e.g., latex orpolyurethane condoms are acceptable) when engaging in sexual activitywith a female of childbearing potential (FCBP) while on Compound 1 andfor at least 28 days after the last dose of study medication. A FCBP isdefined as a sexually mature female who has not undergone a hysterectomyor bilateral oophorectomy or who has not been naturally postmenopausalfor at least 24 consecutive months (i.e., who has had menses at any timein the preceding 24 consecutive months); 10. All FCBPs must have anegative pregnancy test at Screening and Day 1. Any FCBP who engages inactivity in which conception is possible must use two forms ofcontraception simultaneously while on Compound 1 and for at least 28days after taking the last dose of Compound 1: one highly effective form(i.e., hormonal, intrauterine device, tubal ligation, vasectomizedpartner) and one additional form (latex condom or any nonlatex condomNOT made of natural [animal] membrane [e.g., polyurethane], diaphragm,sponge). If one highly effective form of contraception cannot be used,then two forms of barrier contraception must be used, i.e., latex condomor any nonlatex condom NOT made out of natural (animal) membrane [e.g.,polyurethane] with either of the following: sponge with spermicide ordiaphragm with spermicide; 11. Female subjects that are postmenopausal(defined as 24 months without menses before Screening, with an estradiollevel of <30 pg/mL and FSH level of >40 IU/L at Screening).

Exclusion Criteria.

Potential subjects will be excluded from enrollment if any of thefollowing occur: 1. Exposed to an investigational drug (new chemicalentity) within 30 days preceding the first dose of Compound 1administration, or five half-lives of that investigational drug, ifknown (whichever is longer); 2. Subjects who are part of the clinicalstaff personnel or family members of the study site staff, 3. ScreeningFVC<40% predicted; 4. Screening DLco<20% predicted; 5. Any conditionother than pulmonary fibrosis that is likely to result in the subject'sdeath or increases the risk of death within a year from signing the ICF;6. Known clinical diagnosis of pulmonary arterial hypertension thatcurrently requires treatment; 7. Subjects with cystic fibrosis, activeaspergillosis, active tuberculosis, or other serious concomitantrespiratory disorder other than pulmonary fibrosis, as determined by theInvestigator. Subjects with reactive airway disease, chronic obstructivepulmonary disease, and asthma may be included as long as, in the opinionof the Investigator, fibrosis is the major contributing factor to thesubject's respiratory disorder; 8. Use of any cytotoxic agents within 4weeks of dosing. 9. Currently being administered any targeted therapyfor pulmonary fibrosis and not on a stable dose for ≥6 weeks durationprior to first study dosing (potential subjects should be excluded if adose increase is planned during the study period); 10. Use of Esbriet®(pirfenidone) or Ofev® (nintedanib) within 30 day prior to first dose;11. Currently being administered statins (HMG-CoA reductase inhibitors)and not on a stable dose for ≥6 weeks duration prior to first studydosing (potential subjects should be excluded if a dose increase isplanned during the study period); 12. Taking medications that aresubstrates of the transporters P-gp, BCRP, OAT3, OATP1B1, OATP1B3, andOCT2 and have a narrow therapeutics index (e.g., P-gp substratedigoxin); 13. Use of acetaminophen (paracetamol) at a dosage>3 grams perday within 2 weeks of first study dosing; 14. Use of niacin at adosage>2 grams/day within 2 weeks prior to first study dosing; 15. Anysignificant medical condition, laboratory abnormality, or psychiatricillness that would prevent the subject from participating in the study;16. History of recurrent bacterial infections (at least three majorinfections resulting in hospitalization and/or requiring intravenousantibiotic treatment within the past 2 years); 17. History of HIV, HBV,or HCV. Subjects treated for HCV who have a sustained virologic responseof 6 months following final HCV treatment can be included; 18. Historyof active malignancy within 5 years prior to signing the ICF, excludingnonmelanoma skin cancer.

6.10. Salt Screening 6.10.1. Solid State Characterization of Salts

The physicochemical properties of Compound 1 free base and salts aresummarized in The physicochemical property assessment includedcrystallinity, melting point, solubility in water and simulated gastricfluid (SGF, without Pepsin), hygroscopicity, accelerated physical andchemical stability in the solid state under stress conditions. Thephysicochemical properties for the free base and salts of Compound 1 aresummarized in Table 38. Among salts and free base evaluated, thephosphate salt showed better physicochemical properties.

The details were presented in the following sections.

¹H NMR: A portion of the sample was dissolved in dimethyl sulfoxide(DMSO-d₆) (containing TMS) and tested using the NMR spectrometer with 32or 64 scans.

Elemental Analysis: Elemental analyses on the salts were performed byIntertek Pharmaceutical Services/QTI.

Raman: A portion of the sample was placed on a Rigaku zero-backgroundXRPD sample holder and analyzed using Raman in reflection mode. Theconditions were indicated as follows:

exposure time: 2 seconds;

accumulations: 2;

magnitude: 10×; and

laser power: 300 mW.

XRPD: A portion of the sample was placed on a Rigaku zero-backgroundXRPD sample holder and analyzed using XRPD from 3-40 degree 2 thetaangle at a speed of 5 degree/min with 40 kV and 44 mA.

Simultaneous TGA/DSC: A portion of the sample was loaded into analuminum (Al) crucible and tested using the TGA/DSC system at a heatingrate of 10° C./min. An empty Al pan was used as blank.

DSC: A portion of the sample was weighed into an Al sample pan, crimpedwith a pin-holed Al lid and tested using the DSC Q1000 system at aheating rate of 10° C./min. An empty Al pan with lid was used asreference.

TGA: A portion of the sample was loaded to an Al sample pan and testedusing the TGA Q500 system at a heating rate of 10° C./min.

DVS: A portion of the sample was loaded into a quartz sample holder andtested using DVS-Advantage system in two continuousadsorption/desorption cycles. The settings are described as follows:

Solvent: water;

Temperature: 25° C.;

Adsorption/desorption cycle 1: 50 to 95 to 0% RH;

Adsorption/desorption cycle 2: 0 to 95 to 0% RH;

Step size: 10% RH; and

dm/dt (%/min): 0.001 in 15 min with a minimum of 10 min and a maximum of180 min.

PLM: A portion of the sample was placed on a clear glass slide,dispersed with silicon oil and examined under the microscope with 10×subject and transmitted light.

Solubility in Water and SGF: A portion of the sample was weighed into a2 mL clear HPLC vial. After added with water of 1 mL, the vial wascapped and shaken on an orbital shaker at 300 RPM at ambient temperaturefor 24 hours. The sample was removed from the shaker and pH measurementwas performed using a calibrated pH meter. Then a portion of the samplewas filtered using 0.2 m Nylon-membraned centrifuge tube filter at 14000RPM for 5 min. The filtrate was analyzed using HPLC/UV with appropriatedilution. The filtered solid residues were analyzed using XRPD.

For solubility in SGF, the samples were prepared and assayed in the sameprocedures as mentioned above.

6.10.2. Summary of Salts

Salt screening was performed on Compound 1 using 13 acidic counter-ionsand a variety of solvents. The crystalline salts obtained werehydrochloride (HCl), sulfate (H₂SO₄), phosphate (H₃PO₄), L-tartrate,L-malate, L-lactate, succinate, p-toluenesulfate (tosylate),methanesulfate (mesylate), benzensulfate (besylate) and fumarate. Anamorphous salt was obtained when citric acid was used as thecounter-ion. Multiple forms or polymorphs were observed for most of thecrystalline salts. The results of the salt screen are summarized inTable 37.

TABLE 37 Summary of Salt Screening Results for Compound 1. 04 05 06Sample 01 HCl 02 H₂SO₄ 03 H₃PO₄ L-lactic L-tartaric L-malic A salt, form1, salt, form 1 salt, form 1 free base, salt, form 1, salt, form 1hydrate form C hydrate B salt, form 2, salt, form 1 salt, salt salt,form 1 salt, form 1 salt, form anhydrate form 1 hydrate 2, w/ MeNO₂ Csalt, form 3, salt, form 1 salt, form 1 salt, form 2 salt, form 1, salt,form w/trace hydrate 3, w/ EtOAc EtOAc D salt, salt, form 2 salt, form 1free base, salt, form 1, salt, form form 4, form B, hydrate, w/ 4, w/IPA w/trace w/Acetone trace Acetone Acetone 12 Free Sample 07 Citric 08Succinic 09 PsOH 10 MsOH 11 L-aspartic base A salt, w/ trace salt, form1 salt, form 1 salt, form free base, form C, ACN w/ ACN 1, w/ IPA formC, w/ w/ACN ACN B salt, w/ trace salt, form 1 salt, form 2 salt, formmix of free form C, MeNO₂ w/ EtOH 1, w/ IPA base form B w/EtOH &(trace), form C IPA (trace) and acid, not stoichiometric C salt salt,form 2 salt, form 3 salt, form 2 mix of free form G, w/ EtOAc base formC, w/EtOAc form G and acid, not stoichiometric D salt, w/ mix of salt,form 2 salt, form free base, form B, MeOAc succinic salt 1, w/ form C,w/Acetone form 1 and Acetone w/Acetone free base form B Notes: Citratesalts are amorphous. Initial re-crystallization solvents: A = ACN, B =EtOH, C = EtOAc, D = Acetone. Free base: form A (initial material), formD (MeOH solvate). The free base Forms A, Form B, Form C and Form G werepreviously described in U.S. Provisional Patent Application No.61/933,636, filed on Jan. 30, 2014, and U.S. Provisional PatentApplication No. 62/025,161, filed on Jul. 16, 2014. MeOAc = methylacetate, EtOAc = ethyl acetate, ACN = acetonitrile, EtOH = ethanol, MeOH= methanol, MeNO₂ = nitromethane, IPA = isopropanol, PsOH =p-toluenesulfonic acid, MsOH = methanesulfonic acid. Additionalcrystalline salts obtained: besylate and fumarate.

The physicochemical property assessment included crystallinity, meltingpoint, solubility in water and simulated gastric fluid (SGF, withoutPepsin), hygroscopicity, accelerated physical and chemical stability inthe solid state under stress conditions. The physicochemical propertiesfor the free base and salts of Compound 1 are summarized in Table 38.Among salts and free base evaluated, the phosphate salt showed betterphysicochemical properties.

TABLE 38 Summary of Physicochemical Properties for Compound 1 Free Baseand Salts. Property Free base HCl H₂SO₄ H₃PO₄ Number of forms observed 57 3 1 Form evaluated form A form 2 form 1 form 1 Water/Solvent (%) 0.22(TGA to 2.82 (TGA to 0.28 (TGA to 0.25 (TGA to 119.9° C.) 119.9° C.)119.9° C.) 119.9° C.) Melting Point (° C., DSC onset 223.1 Endothermic235.0 238.3 temperature) (melting) peak at 163.0; (melting & (melting &melting & decomp.) decomp.) decomp at 264.0 Solubility (mg/mL, In water0.018 (pH 8.96) 10.761 (pH 3.87) 2.647 (pH 1.69) 5.433 (pH 4.50) equiv.to free base) In SGF 7.167 (pH 2.20) 6.058 (pH 1.19) 3.187 (pH 1.03)9.157 (pH 1.44) Hygroscopicity (80% RH, 0.17 5.21 6.13 0.48 25° C.,cycle 1 sorption) Physical stability 80° C. no change no change nochange no change (open vial, 2 weeks) 80° C./75% no change form changeform change no change RH Chemical stability 80° C. no change no changeno change no change (open vial, 2 weeks) 80° C./75% no change no changeno change no change RH Property L-tartrate L-malate L-lactate Number offorms observed 2 4 2 Form evaluated form 1 form 2 form 2 Water/Solvent(%) 3.97 (water, 1.25 (TGA to 1.74 (TGA to TGA to 119.9° C.) 119.9° C.)119.9° C.) Melting Point (° C., DSC onset Dehydration at Multiple eventsat 145.3 temperature) 89.5; melting & 100.8 and 163.2 (decomp.) decompat 219.9 Solubility (mg/mL, In water 0.405 (pH 5.35) 4.496 (pH 4.07)4.220 (pH 4.52) equiv. to free base) In SGF 9.223 (pH 1.59) 8.922 (pH1.54) 9.529 (pH 1.67) Hygroscopicity (80% RH, 0.81 5.60 2.65 25° C.,cycle 1 sorption) (hydrate) Physical stability 80° C. no change formchange form change (open vial, 2 weeks) 80° C./75% no change form changeform change RH Chemical stability 80° C. no change ~12% degradation nochange (open vial, 2 weeks) 80° C./75% no change  ~7% degradation nochange RH

6.10.3. Preparation of the Salts

The concentration of 0.12 mol/L was used for all acids except forL-aspartic acid. HCl, H₂SO₄, H₃PO₄, L-lactic acid, methanesulfonic acidand benzenesulfonic acid were prepared in ACN, L-tartaric acid, L-malicacid, citric acid, succinic acid, p-toluenesulfonic acid and fumaricacid were prepared in MeOH. L-aspartic acid (0.03 mol/L) was prepared inwater. Compound 1 (free base) of 604.8 mg was dissolved inmethanol/dichloromethane (MeOH/DCM, 1/1 v/v pre-mixed) of 50 mL,resulting in a clear solution with concentration of 12.1 mg/mL aftersonicated for 5 min. This was used for the salt preparations except forbesylate and fumarate samples.

The salt samples were prepared based on a stoichiometric ratio of 1:1.05for free base to acid. An aliquot of 1.04 mL of free base solution(i.e., 0.039 mmole of free base) was mixed with 0.342 mL of acid (i.e.,0.041 mmole of acid) to obtain one salt sample in a 2 mL or 4 mL clearglass vial. Four salt samples for each acid were prepared in the sameprocedure.

As to the besylate and fumarate samples, Compound 1 (free base) of 33.3mg was dissolved in 2 mL of MeOH/dichloromethane to generate a solutionof 16.7 mg/mL. One mL of free base solution was mixed with 0.453 mL ofacid to obtain a salt sample, resulting in only one sample for eachacid.

The preparation of the salt samples comprised the steps of:

1) covering (for 2 mL vials) or capping (for 4 mL vials) the sample vialcontaining the solution of Compound 1 and shaking on an orbital shakerat 150 RPM at ambient temperature for 2 hours;

2) removing cover or caps;

3) evaporating the solvent in the sample vials under nitrogen purge in afume hood;

4) adding ACN, EtOH, EtOAc or acetone to 4 sample vials, respectively,corresponding to each acidic counter-ion based on the one-solvent forone-sample fashion;

5) adding an acidic counter-ion;

6) covering or capping and shaking the samples vial at 200 RPM atambient temperature for 24 hours;

7) removing cover and caps;

8) evaporating the solvent in the sample vials under nitrogen purge in afume hood;

9) adding additional solvent in attempt to generate powder-like solidsif no powder-like solids were visually observed upon dried;

10) filtering the sample using 0.45 m Nylon-membraned centrifuge tubefilter at 14000 RPM for 5 min if powder-like solids were visuallyobserved during drying;

11) collecting and drying the solids in a closed chamber connected tohouse vacuum for 2 hours; and

12) harvesting the solids at the end.

The solids were subjected to analysis using Raman, XRPD, proton NMR (¹HNMR), TGA/DSC and/or PLM.

6.10.4. Elemental Analysis

Elemental analysis results are presented in Table 39. They are inagreement with the theoretical values for the tested elements.

TABLE 39 Elemental Analysis Results of Compound 1 Salts Sample ElementHCl Salt Form 2 % C % H % N % Cl Theoretical 53.70 7.89 19.57 9.91Experimental 51.72 8.15 18.74 9.24 Difference −1.98 0.26 −0.83 −0.67H₂SO₄ Salt Form 1 % C % H % N % S Theoretical 45.81 6.97 16.69 7.64Experimental 45.39 6.94 16.44 8.38 Difference −0.42 −0.03 −0.25 0.74H₃PO₄ Salt Form 1 % C % H % N % P Theoretical 45.82 7.21 16.70 7.39Experimental 45.80 7.24 16.54 7.59 Difference −0.02 0.03 −0.16 0.20L-tartrate Salt Form 2 % C % H % N Theoretical 52.16 7.78 16.90Experimental 50.95 7.65 16.40 Difference −1.21 −0.13 −0.50 L-malate SaltForm 2 % C % H % N Theoretical 52.74 7.30 15.37 Experimental 52.07 7.3715.71 Difference −0.67 0.07 0.34 L-lactate Salt Form 2 % C % H % NTheoretical 55.46 8.08 17.02 Experimental 55.36 8.22 16.69 Difference−0.10 0.14 −0.33 Note: Theoretical calculations for L-tartrate werebased on hemi-tartrate dihydrate.

6.10.5. Salt Screening Results

As presented in Table 37, crystalline salts were obtained for the acids,HCl, H₂SO₄, H₃PO₄, L-tartaric acid, L-lactic acid, L-malic acid,succinic acid, p-toluenesulfonic acid and methanesulfonic acid. Anamorphous salt was obtained for citric acid.

Based on XRPD and Raman data, multiple forms were observed for the saltsexcept that the H₃PO₄ salt and L-tartrate salt. ¹H NMR and simultaneousTGA/DSC indicated some forms contained water or organic solvents.

6.10.5.1. HCl Salt of Compound 1

Totally 7 different forms of the HCl salt were prepared.

In summary, seven forms of HCl salt were prepared as follows:

HCl salt form 1: hydrate, obtained through crystallization in ACN, orsuspended in SGF or exposed to moisture;

HCl salt form 2: contained water, obtained through crystallization inEtOH/IPA or IPA, converted to hydrate when exposed to moisture (toform 1) or suspended in water (to form 7);

HCl salt form 3: obtained through crystallization in EtOAc;

HCl salt form 4: obtained through crystallization in acetone;

HCl salt form 5: obtained though heating form 2 to 180° C., converted tohydrate form 1 when exposed to moisture;

HCl salt form 6: dehydrate hydrate, obtained though heating form 2 to220° C., converted to hydrate form 1 when exposed to moisture; and

HCl salt form 7: hydrate, obtained though suspending form 1 in water atambient temperature.

The XRPD patterns and Raman spectra of HCl salt forms 1-4 of Compound 1are provided in FIG. 6 and FIG. 7, respectively.

HCl salt form 1 had a crystalline XRPD pattern as shown in FIG. 75.

A list of X-Ray Diffraction Peaks for HCl salt form 1 is provided belowin Table 40.

TABLE 40 X-Ray Diffraction Peaks for HCl salt form 1 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 5.516.0 12969.1 2068.1 7.5 11.7 1916.6 177.6 9.0 9.8 1288.7 164.0 9.7 9.14706.0 846.5 11.2 7.9 7392.3 1379.4 13.1 6.8 6097.3 1064.5 13.9 6.32629.6 396.9 15.9 5.6 1838.4 262.7 16.5 5.4 2214.5 355.6 17.2 5.2 5130.21766.5 17.3 5.1 5855.7 1237.4 18.3 4.8 17932.2 3594.4 19.6 4.5 15494.73471.5 19.8 4.5 2868.8 806.8 21.7 4.1 14631.1 3058.6 22.0 4.0 2354.4290.7 22.9 3.9 3438.0 1080.1 23.7 3.7 7449.4 1796.7 24.6 3.6 687.9 124.324.9 3.6 2183.3 439.3 25.9 3.4 5740.1 927.3 26.4 3.4 758.8 192.3 27.33.3 709.7 52.8 27.7 3.2 3379.1 765.1 28.2 3.2 4483.6 1063.5 28.5 3.11718.2 451.3 29.9 3.0 1186.0 187.7 30.6 2.9 4778.8 849.3 31.0 2.9 579.1142.9 31.2 2.9 1004.1 293.2 31.7 2.8 3247.0 607.3 32.0 2.8 490.8 40.232.6 2.7 1788.3 320.3 33.0 2.7 2215.9 521.6 33.4 2.7 1783.0 343.1 33.72.7 905.0 191.9 34.2 2.6 459.8 77.8 36.3 2.5 1031.8 281.1 37.8 2.4 938.8168.8 38.8 2.3 1982.7 408.2

HCl salt form 2 had a crystalline XRPD pattern as shown in FIG. 76. Alist of X-Ray Diffraction Peaks for HCl salt form 2 is provided below inTable 41.

TABLE 41 X-Ray Diffraction Peaks for HCl salt form 2 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 5.3716.45 592.55 653.57 7.92 11.15 35976.02 7129.51 9.23 9.57 12118.242899.30 9.53 9.27 1421.61 374.75 11.95 7.40 3305.19 604.45 12.40 7.133829.96 761.05 12.61 7.01 3151.61 620.59 13.09 6.76 2672.35 447.18 14.905.94 1349.67 281.34 15.69 5.64 453.74 255.32 16.52 5.36 959.65 359.2317.92 4.94 3894.23 592.00 18.17 4.88 1435.64 287.43 18.64 4.76 3595.381089.65 18.94 4.68 7474.81 1966.00 20.54 4.32 2348.09 486.82 20.69 4.299741.77 2458.87 20.93 4.24 2316.35 485.29 21.36 4.16 1483.99 326.2421.69 4.09 2744.34 547.92 22.05 4.03 2192.50 487.17 22.80 3.90 4442.54937.81 23.55 3.77 642.11 115.13 24.28 3.66 4273.40 950.29 24.71 3.602550.28 426.18 25.09 3.55 2388.93 360.05 25.25 3.52 1805.08 1004.7825.78 3.45 2459.67 564.50 25.99 3.43 599.00 135.04 27.02 3.30 3349.83968.94 28.42 3.14 399.55 113.91 28.87 3.09 435.96 108.32 29.63 3.013577.77 1098.93 30.74 2.91 1588.78 574.33 31.58 2.83 605.09 156.91 31.872.81 848.03 124.95 32.33 2.77 377.17 63.59 32.76 2.73 502.69 59.45 33.352.68 875.09 200.67 34.02 2.63 558.64 122.35 35.10 2.55 350.60 235.0436.06 2.49 586.34 82.05 36.61 2.45 1109.37 368.63 37.00 2.43 510.30107.25 37.86 2.37 782.15 154.15 38.10 2.36 325.09 23.66 39.16 2.30726.50 203.98 39.92 2.26 269.71 34.45

HCl salt form 3 had a crystalline XRPD pattern as shown in FIG. 77.

A list of X-Ray Diffraction Peaks for HCl salt form 3 is provided belowin Table 42.

TABLE 42 X-Ray Diffraction Peaks for HCl salt form 3 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 5.7115.47 1872.85 491.40 9.48 9.32 158.22 16.75 9.85 8.98 161.51 41.55 11.347.80 420.89 84.75 13.24 6.68 238.55 53.54 14.10 6.28 127.25 26.40 16.755.29 66.83 49.71 17.86 4.96 41.98 4.90 18.44 4.81 399.82 83.45 19.674.51 187.75 49.56 21.82 4.07 138.69 41.10 23.10 3.85 106.66 26.29 23.843.73 105.12 24.30 25.03 3.55 79.21 9.11 26.04 3.42 76.81 13.09 27.813.21 35.67 26.16 30.65 2.91 24.89 9.32 31.83 2.81 47.28 6.83 38.91 2.3182.80 16.42

HCl salt form 4 had a crystalline XRPD pattern as shown in FIG. 78.

A list of X-Ray Diffraction Peaks for HCl salt form 4 is provided belowin Table 43.

TABLE 43 X-Ray Diffraction Peaks for HCl salt form 4 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 5.6515.63 4924.84 825.47 5.73 15.41 5498.85 591.99 7.50 11.77 279.33 45.509.31 9.49 277.38 51.20 9.77 9.05 764.25 137.09 11.38 7.77 1245.36 192.7313.77 6.43 1857.08 316.92 14.23 6.22 225.80 41.68 16.20 5.47 114.7139.23 17.16 5.16 304.94 111.55 17.54 5.05 177.51 14.77 18.16 4.88 127.7120.78 18.69 4.74 347.52 64.84 19.06 4.65 202.42 29.94 20.56 4.32 90.6521.84 21.65 4.10 1074.30 88.67 21.75 4.08 477.54 24.35 22.10 4.02 92.9717.23 22.65 3.92 68.46 7.91 23.05 3.86 129.05 14.51 24.04 3.70 198.4540.76 26.18 3.40 83.26 32.14 28.30 3.15 92.13 14.64 28.45 3.13 128.7316.20 28.70 3.11 100.53 13.07 29.59 3.02 606.36 75.13 30.90 2.89 53.6428.04 32.47 2.76 60.31 13.68 35.63 2.52 137.84 16.16

HCl salt form 5 had a crystalline XRPD pattern as shown in FIG. 79.

A list of X-Ray Diffraction Peaks for HCl salt form 5 is provided belowin Table 44.

TABLE 44 X-Ray Diffraction Peaks for HCl salt form 5 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 5.6315.69 8757.84 2202.44 6.29 14.03 966.00 355.83 7.61 11.60 877.18 137.618.45 10.46 2316.04 443.76 9.74 9.08 2656.26 542.46 10.76 8.22 1049.40386.31 11.27 7.85 3658.20 726.37 12.23 7.23 846.40 176.62 12.59 7.02283.48 81.70 13.16 6.72 3704.71 860.85 14.02 6.31 1508.74 362.71 14.636.05 2066.39 566.49 15.97 5.54 237.35 56.74 16.63 5.33 878.65 150.2316.92 5.24 699.58 83.76 17.35 5.11 4030.83 1382.01 17.74 5.00 2443.62348.59 18.40 4.82 6073.33 1172.14 18.69 4.74 4103.82 2582.57 19.10 4.642293.83 529.63 19.66 4.51 7592.14 2574.56 21.80 4.07 7719.16 2045.1222.63 3.93 792.18 132.23 23.05 3.86 3608.05 701.52 23.80 3.74 6333.671485.01 24.58 3.62 855.84 285.38 24.98 3.56 1705.94 288.11 25.94 3.434528.66 1061.43 26.51 3.36 1115.02 242.90 27.78 3.21 2251.91 555.9528.25 3.16 2814.48 672.69 28.57 3.12 1083.07 420.02 30.62 2.92 3510.29896.26 31.38 2.85 650.63 288.80 31.78 2.81 1924.51 446.62 32.61 2.741419.18 422.36 33.01 2.71 1024.52 282.57 33.40 2.68 675.21 391.50 35.402.53 566.07 145.81 37.88 2.37 731.57 141.30 38.82 2.32 986.44 438.18

HCl salt form 6 had a crystalline XRPD pattern as shown in FIG. 80.

A list of X-Ray Diffraction Peaks for HCl salt form 6 is provided belowin Table 45.

TABLE 45 X-Ray Diffraction Peaks for HCl salt form 6 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 5.5815.81 31929.40 7867.13 7.61 11.61 2354.93 399.68 8.27 10.68 942.70156.02 9.13 9.67 1041.26 178.68 9.74 9.08 5902.42 1316.22 11.19 7.908964.42 1880.17 13.14 6.73 7139.88 1488.68 13.99 6.32 3397.71 771.6915.91 5.57 1911.79 311.33 16.65 5.32 2298.21 475.14 16.87 5.25 1228.29312.19 17.33 5.11 9891.46 3506.94 18.38 4.82 17540.88 4446.97 19.67 4.5116386.83 4653.87 19.92 4.45 3596.19 952.42 21.79 4.07 15553.47 3148.9521.99 4.04 2610.38 1456.90 23.03 3.86 7569.93 1479.04 23.32 3.81 988.39480.26 23.77 3.74 11655.19 2269.32 24.66 3.61 809.20 131.82 24.97 3.563705.27 646.97 25.33 3.51 824.98 151.05 25.92 3.43 7418.01 1432.81 26.523.36 1905.31 385.66 27.38 3.25 407.44 102.52 27.76 3.21 4154.50 956.3428.24 3.16 6007.39 1332.17 28.54 3.13 2152.95 564.23 30.62 2.92 5038.25963.05 31.34 2.85 824.03 518.33 31.74 2.82 2993.10 591.44 32.63 2.742078.78 362.73 33.04 2.71 1869.26 488.45 33.47 2.68 1096.36 626.44 36.382.47 1154.33 301.56 37.83 2.38 967.95 193.48 38.79 2.32 1459.86 469.44

HCl salt form 7 had a crystalline XRPD pattern as shown in FIG. 81.

A list of X-Ray Diffraction Peaks for HCl salt form 7 is provided belowin Table 46.

TABLE 46 X-Ray Diffraction Peaks for HCl salt form 7 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 5.5415.95 6246.28 1256.69 7.61 11.61 7037.98 595.99 8.95 9.87 1033.78 121.169.85 8.97 1288.63 176.25 11.14 7.94 2359.79 283.51 12.86 6.88 1130.30176.10 14.14 6.26 351.89 124.94 15.77 5.62 665.95 92.06 16.83 5.27844.94 132.97 17.29 5.13 469.56 63.63 17.51 5.06 732.33 101.81 18.044.91 3457.16 535.82 18.33 4.84 533.06 58.91 18.69 4.74 195.55 23.2319.82 4.48 1843.83 457.27 21.94 4.05 1075.92 247.17 23.05 3.85 2919.74372.20 23.90 3.72 986.64 157.89 28.28 3.15 610.86 102.24 30.66 2.91247.39 102.03 32.02 2.79 481.59 79.64 38.98 2.31 1528.36 239.71

In the TGA/DSC thermogram of the HCl salt form 2 (FIG. 34), 2.82% weightloss upon heating to 119.9° C. on TGA is attributed to the water contentin the material. A small endothermic peak at 163.0° C. in DSC thermogramis likely a solid-solid transition followed by melting and decompositionaround 220° C.

The sorption/desorption of HCl salt form 2 is presented in FIG. 41. Itdemonstrated that the current HCl salt (form 2) was hygroscopic innature, and likely formed a monohydrate upon uptaking water. The wateruptake is 4.89% at 40% RH from Cycle 2 sorption isotherm. This is closeto the theoretical value of water content (4.79%) for the HCl saltmonohydrate. It appears that the hydrate is not hygroscopic, but waterdepartures quickly when RH is below 20% even at 25° C. As shown in FIG.42, the XRPD pattern of the post-DVS sample is different from that ofthe initial material.

The XRPD patterns of Compound 1 HCl salt under stress conditions arepresented in FIG. 55. Compared to that of the initial material, the XRPDpattern of HCl salt form 2 stored under 80° C. for 2 weeks remainedunchanged, but the XRPD pattern of HCl salt stored under 80° C./75% RHis different. The results indicated that the current HCl salt isphysically stable under 80° C. dry condition, but not stable under wetcondition.

The HCl salt form 2 was heated in DSC to 180° C. at 10° C./min. Ramanand XRPD were immediately run for the solid residues at the end of DSCrun when the sample pan was unloaded between 35-45° C. Afterwards, thesolid residues were stored at 40° C./75% RH up to 6 days and testedusing XRPD.

The HCl salt form 2 was heated in DSC to 220° C. at 10° C./min. Ramanand XRPD were immediately run for the solid residues at the end of DSCrun when the sample pan was unloaded between 35-45° C. Afterwards, thesolid residues were stored at 40° C./75% RH up to 64 hours and testedusing XRPD.

As indicated by Raman in FIG. 56 and XRPD in FIG. 57, two new forms ofHCl salts were obtained when HCl salt form 2 was heated to 180° C. and220° C., respectively. They were designated as form 5 for the materialheated to 180° C. and form 6 for the material heated to 220° C. Afterbeing stored at 40° C./75% RH, the two forms showed the same XRPDpatterns as that of unheated HCl salt (initial material) stored in thesame condition for 2 weeks. This demonstrated that form 5 and form 6tended to become hydrates when exposed to moisture at 40° C. It wasconfirmed by TGA/DSC (FIG. 58) that the sample of the HCl salt stored at40° C./75% RH for the physical stability test was an hydrate. Asindicated by XRPD in FIG. 57, the hydrate is different from the solidresidue (tentatively assigned as form 7) obtained from solubility testof the HCl salt in water.

Simultaneous TGA/DSC was also conducted on HCl salt (form 2) by heatingit to 220° C., cooling back to 25° C. and then heating to 280° C. Theheating/cooling rate was 10° C./min. The TGA/DSC thermograms werepresented in FIG. 59. From the first heating process, a weight loss of2.91% was observed from TGA up to 131.2° C. No weight loss or otherthermal events were observed during second heating up to 210° C.,showing that form 6 (HCl salt heated to 220° C.) did not contain water.Form 1 of HCl salt was first obtained through crystallization using ACN(no ACN contained in the sample based on ¹H NMR), and it was likely thesame material as HCl salt suspended in SGF or exposed to moisture. Asshown in FIG. 60, form 1 appeared to be a hydrate. Since form 6 did notcontain water but converted to a hydrate when exposed to moisture, itwas likely a dehydrate hydrate.

6.10.5.2. H₂SO₄ Salt of Compound 1

H₂SO₄ salt form 1 was prepared by evaporation of a solution comprisingCompound 1 and H₂SO₄ in ACN, IPA or EtOAc. H₂SO₄ salt form 2 wasprepared by evaporation of a solution comprising Compound 1 and H₂SO₄ inacetone.

The XRPD patterns and Raman spectra of H₂SO₄ salt forms 1-2 of Compound1 are provided in FIG. 8 and FIG. 9, respectively.

H₂SO₄ salt form 1 had a crystalline XRPD pattern as shown in FIG. 82.

A list of X-Ray Diffraction Peaks for H₂SO₄ salt form 1 is providedbelow in Table 47.

TABLE 47 X-Ray Diffraction Peaks for H₂SO₄ salt form 1 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 5.4016.35 22092.62 7232.95 5.66 15.61 1917.86 1455.52 9.02 9.79 528.92 86.3310.74 8.23 6630.92 1762.86 14.78 5.99 1863.07 506.47 16.16 5.48 3763.67955.60 16.65 5.32 843.38 287.96 17.65 5.02 1373.47 1338.01 18.18 4.8818989.96 3922.05 18.69 4.74 10432.71 2885.01 19.67 4.51 2121.35 450.5020.50 4.33 930.91 322.41 21.62 4.11 8852.02 2582.96 22.28 3.99 12575.422783.45 22.75 3.91 8651.16 2341.73 24.13 3.69 5109.83 1395.18 24.57 3.62930.19 210.07 24.88 3.58 3420.54 811.66 25.42 3.50 1458.25 964.96 26.553.35 9457.08 2103.26 28.49 3.13 1137.23 182.53 29.17 3.06 982.32 358.9529.88 2.99 1812.40 495.30 31.29 2.86 693.51 325.31 32.15 2.78 1179.11251.18 32.66 2.74 871.43 185.29 33.21 2.70 717.07 238.85 34.02 2.63736.56 453.03 35.78 2.51 444.20 64.31 36.86 2.44 435.04 57.67 37.43 2.40497.72 81.14 38.27 2.35 1574.41 354.26 39.64 2.27 568.60 217.43

H₂SO₄ salt form 2 had a crystalline XRPD pattern as shown in FIG. 83.

A list of X-Ray Diffraction Peaks for H₂SO₄ salt form 2 is providedbelow in Table 48.

TABLE 48 X-Ray Diffraction Peaks for H₂SO₄ salt form 2 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 5.6315.68 1997.46 493.57 5.67 15.57 487.80 287.88 15.25 5.80 131.71 29.7016.08 5.51 58.35 31.09 17.87 4.96 504.85 129.56 18.57 4.77 165.17 65.8921.83 4.07 55.13 16.10 22.24 3.99 154.81 35.67 22.75 3.91 92.30 47.7825.90 3.44 69.67 14.82 26.53 3.36 29.58 6.94 27.18 3.28 104.25 20.4211.30 N/A N/A N/A

In the TGA/DSC thermogram of the H₂SO₄ salt form 1 (FIG. 35), 0.28%weight loss upon heating to 119.9° C. on TGA is attributed to the traceamount of water in the material. A small T_(g)-like event between 86.0°C. and 88.4° C. in DSC thermogram was noticed and no furtherinvestigation was carried out in this study. TGA thermogram indicated acontinuous weight loss starting from 119.9° C., while DSC indicatedsignificant melting and decomposition started around 220° C.

The sorption/desorption of H₂SO₄ salt form 1 is presented in FIG. 43. Itdemonstrated that the current H₂SO₄ salt (form 1) was hygroscopic innature. As shown in FIG. 44, the XRPD pattern of the solid residuesafter DVS test is different from that of the initial material.

The XRPD patterns of Compound 1 H₂SO₄ salt under stress conditions arepresented in FIG. 61. Compared to that of the initial material, the XRPDpattern of H₂SO₄ salt stored under 80° C. for 2 weeks remainedunchanged, but the XRPD pattern of H₂SO₄ salt stored under 80° C./75% RHis different. The results indicated that the current H₂SO₄ salt isphysically stable under 80° C. dry condition, but not stable under wetcondition. Chemical stability indicated that H₂SO₄ salt was stable understress conditions, therefore a new form (form 3) of H₂SO₄ salt wasobtained when it was stored under 80° C./75% RH conditions for 2 weeks.

H₂SO₄ salt form 3 had a crystalline XRPD pattern as shown in FIG. 84.

A list of X-Ray Diffraction Peaks for H₂SO₄ salt form 3 is providedbelow in Table 49.

TABLE 49 X-Ray Diffraction Peaks for H₂SO₄ salt form 3 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 5.6015.76 84043.67 19286.01 17.67 5.01 16887.29 3444.96 11.22 7.88 7847.261712.69 22.38 3.97 3043.71 979.78 15.11 5.86 3007.89 721.89 18.10 4.902286.45 650.14 22.61 3.93 2056.14 616.97 22.10 4.02 3141.47 606.73 27.243.27 2752.01 581.93 10.68 8.28 2639.54 568.81 18.48 4.80 2269.44 418.7615.96 5.55 1726.73 404.85 21.53 4.12 1594.47 390.21 25.85 3.44 1080.69359.32 25.22 3.53 1119.71 331.14 24.56 3.62 1385.37 299.12 23.65 3.761005.15 268.82 19.15 4.63 901.20 225.40 12.41 7.13 1028.08 166.69 26.273.39 588.43 121.97 18.78 4.72 422.19 99.28 13.81 6.41 429.52 84.84 34.202.62 382.23 81.71 16.86 5.26 185.84 79.25 33.38 2.68 305.57 71.79 37.962.37 174.37 40.85

6.10.5.3. H₃PO₄ Salt of Compound 1

The H₃PO₄ salt of Compound 1 was prepared by evaporation of a solutioncomprising Compound 1 and H₃PO₄ in ACN, EtOH, EtOAc or acetone.

The XRPD pattern and Raman spectrum of H₃PO₄ salt of Compound 1 areprovided in FIG. 10 and FIG. 11, respectively.

H₃PO₄ salt had a crystalline XRPD pattern as shown in FIG. 85.

A list of X-Ray Diffraction Peaks for H₃PO₄ salt is provided below inTable 50.

TABLE 50 X-Ray Diffraction Peaks for H₃PO₄ salt Integrated IntensityTwo-theta angle (°) d Space (Å) Height (cps) (cps deg) 5.58 15.82113896.47 43662.53 5.73 15.42 83115.98 17172.19 11.30 7.83 22604.948264.42 15.27 5.80 12217.79 4303.97 16.07 5.51 1220.72 227.74 16.37 5.412410.31 1008.88 16.95 5.23 9098.15 3097.79 17.46 5.08 1398.63 350.3217.72 5.00 5630.55 1749.92 18.37 4.82 5749.42 1742.60 20.64 4.30 1222.06517.32 20.98 4.23 4045.16 1304.81 21.73 4.09 2784.49 975.76 22.34 3.982069.88 521.03 22.66 3.92 5785.47 1825.70 23.31 3.81 3257.99 950.9823.65 3.76 9545.98 2616.01 24.14 3.68 1799.94 1196.49 25.88 3.44 7708.993286.84 26.42 3.37 3658.44 972.03 28.10 3.17 444.85 279.86 28.39 3.1411434.58 3320.53 29.89 2.99 1225.03 328.89 30.38 2.94 615.58 136.3830.88 2.89 1948.99 689.16 31.35 2.85 2657.30 881.21 33.13 2.70 586.48275.45 34.32 2.61 1351.06 388.17 35.08 2.56 685.02 252.22 35.91 2.50804.38 245.10 37.43 2.40 449.17 119.67 38.89 2.31 1307.87 709.00

In the TGA/DSC thermogram of the H₃PO₄ salt (FIG. 36), 0.25% weight lossupon heating to 119.9° C. in TGA is attributed to the trace amount ofwater in the material. TGA results indicated a continuous weight lossstarting from around 169.9° C., while DSC indicated melting anddecomposition with an onset temperature of 238.3° C.

The sorption/desorption of H₃PO₄ salt is presented in FIG. 45,indicating that H₃PO₄ salt is not hygroscopic. As shown in FIG. 46, theXRPD pattern of the solid residues after DVS test remained unchangedfrom that of the initial material.

The XRPD patterns of Compound 1 H₃PO₄ salt under stress conditions arepresented in FIG. 62. Compared to that of the initial material, the XRPDpatterns of H₃PO₄ salt remained the same as that of the initialmaterial, showing that it was physically stable under 80° C. and 80°C./75% RH conditions for 2 weeks.

6.10.5.4. L-Tartrate Salt of Compound 1

The L-tartrate salt of Compound 1 was prepared by evaporation of asolution comprising Compound 1 and L-tartaric acid in ACN, EtOH, EtOAcor acetone.

The XRPD pattern and Raman spectrum of the L-tartrate salt of Compound 1are provided in FIG. 12 and FIG. 13, respectively.

L-tartrate salt form 1 had a crystalline XRPD pattern as shown in FIG.88.

A list of X-Ray Diffraction Peaks for L-tartrate salt form 1 is providedbelow in Table 51.

TABLE 51 X-Ray Diffraction Peaks for L-tartrate salt form 1 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 6.0414.62 35641.02 13962.89 9.47 9.33 498.71 113.50 12.14 7.28 8910.132777.20 13.73 6.44 1380.04 819.25 14.57 6.07 5574.18 1460.05 15.19 5.835555.62 1613.38 16.19 5.47 27183.97 7267.10 16.68 5.31 14358.85 4281.4017.30 5.12 13416.42 3458.95 18.27 4.85 4471.36 1050.50 19.98 4.4423979.41 9001.06 20.31 4.37 11804.09 3991.55 21.14 4.20 1301.63 239.9722.08 4.02 1347.34 442.01 22.75 3.90 5360.97 2162.43 23.21 3.83 3574.023882.23 23.84 3.73 11453.82 2990.70 24.33 3.66 18815.15 6865.32 25.923.43 1449.30 312.77 26.51 3.36 1104.03 183.82 27.09 3.29 1496.66 230.4027.75 3.21 2573.67 1246.17 28.44 3.14 2470.19 678.86 29.52 3.02 4293.561403.94 31.15 2.87 1948.85 631.58 31.83 2.81 2876.44 853.94 32.73 2.731501.50 473.39 33.31 2.69 1944.21 550.61 34.99 2.56 3591.42 1161.3435.55 2.52 1870.73 746.99 36.80 2.44 822.22 280.25 37.25 2.41 692.53113.17 37.77 2.38 2489.26 741.25 38.41 2.34 449.34 44.89

L-tartrate salt form 2 had a crystalline XRPD pattern as shown in FIG.89.

A list of X-Ray Diffraction Peaks for L-tartrate salt form 2 is providedbelow in Table 52.

TABLE 52 X-Ray Diffraction Peaks for L-tartrate salt form 2 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 5.0217.58 735.02 463.76 6.29 14.04 22630.03 8352.94 6.46 13.67 2622.262491.62 9.71 9.10 1759.68 647.27 12.47 7.09 224.77 399.99 12.63 7.004859.90 1705.70 15.21 5.82 1978.51 1241.29 16.51 5.36 15847.76 6108.0916.56 5.35 907.28 949.99 17.23 5.14 9095.92 2351.90 18.82 4.71 2721.51994.01 20.72 4.28 6070.37 5681.20 22.49 3.95 1617.44 558.47 22.71 3.91567.93 116.48 24.04 3.70 5177.14 3429.03 24.86 3.58 1422.20 220.06 24.953.57 4293.73 1743.64 27.08 3.29 1155.04 620.23 28.25 3.16 1480.68 843.5029.30 3.05 1607.84 780.71 30.78 2.90 319.68 186.67 31.16 2.87 516.2254.50 31.30 2.86 224.24 42.92 33.13 2.70 558.74 250.00 33.96 2.64 300.8931.99 34.36 2.61 338.44 70.34 34.87 2.57 234.44 41.74 35.03 2.56 472.0623.44 35.14 2.55 480.05 28.62 35.29 2.54 274.42 37.01 36.36 2.47 572.04197.04 36.58 2.45 536.59 139.95

The L-tartrate salt was a hemi-tartrate dihydrate as indicated from ¹HNMR in FIG. 14 and TGA/DSC in FIG. 15. The ¹HNMR indicated astoichiometric ratio of approximately 2:1 for the Compound 1 free baseto L-tartaric acid. The TGA/DSC indicated similar weight loss anddissolvation event when different solvents were used forre-crystallization of L-tartrate salt, which indicated that it was ahydrate.

In the TGA/DSC thermogram of the L-tartrate salt (FIG. 37), 3.97% weightloss upon heating to 119.9° C. on TGA is attributed to the water contentin the material. It's corresponding to a dehydration event in DSC withan onset temperature of 89.5° C. This showed that the sample was likelya dihydrate with theoretical value of 4.34% for water content. Thedehydrated product melt and decomposed starting around 201.5° C. asevidenced in both TGA and DSC.

The sorption/desorption of L-tartrate salt is presented in FIG. 47. TheL-tartrate is a hydrate, but water is partially lost when dried invacuum oven during salt preparation. Upon exposed to moisture insorption test, uptaken water is first consumed to satisfy the hydrateformation, therefore the L-tartrate hydrate is only slightlyhygroscopic. As shown in FIG. 49, the XRPD pattern of the solid residuesafter DVS test remained unchanged from that of the initial material.Additional DVS study was performed by pre-heating the L-tartrate salt at50° C. for 3 hours, immediately started the two-cyclesorption/desorption process (i.e., 0-95-0-95-0% RH). Weight loss of5.53% was greater than 3.97% observed in TGA for the initial material,showing that L-tartrate salt re-gained water quickly after withdrawnfrom the vacuum oven. The sorption/desorption isotherms after pre-heatwas presented in FIG. 48, clearly demonstrated that a hydrate was formedquickly even at RH as 20% RH. The test reaches 20% RH in less than 2hours. Cycle 1 sorption at 20% RH was 4.32%, which matches well with thetheoretical value of water content (4.34%) in a hemi-tartrate dihydratesalt. The water uptake of the hydrate at 80% RH is estimated as 0.81%(i.e. the difference between 20% RH and 80% RH at Cycle 1 sorption). Thesorption/desorption is reproducible through Cycle 2 sorption/desorptionat 25° C. At the end of DVS test, the solid residues remained the sameXRPD patterns as those of the initial material and the solids fromprevious DVS test without pre-heating step.

As presented in FIG. 63, the XRPD patterns of Compound 1 L-tartrate saltunder stress conditions remained the same as that of the initialmaterial, showing that it was physically stable under 80° C. and 80°C./75% RH conditions for 2 weeks.

A combinational XRD-DSC experiment was carried out on the L-tartratesalt by heating the sample at 5° C./min and scan XRD at 12°/min 2 theta.The data were illustrated in FIG. 64. XRPD pattern (left side) waschanged between 96.5° C. and 131.5° C., corresponding to an endothermicpeak observed in DSC (right side). It demonstrated the dehydrationoccurred within the temperature range, resulting in an anhydrate.

In order to isolate the L-tartrate salt anhydrate, a portion ofL-tartrate salt was heated in DSC to 130° C. at 10° C./min. The solidresidue was immediately analyzed using XRPD. As shown in FIG. 65, theXRPD patterns were identical for the materials before and after heating,implying the anhydrate picks up moisture rapidly to form the hydrate.Therefore, the hydrate is more stable than the anhydrate.

6.10.5.5. L-Lactate Salt of Compound 1

L-lactate salt form 1 was prepared by evaporation of a solutioncomprising Compound 1 and L-lactic acid in hexane. L-lactate salt form 2was prepared by evaporation of a solution comprising Compound 1 andL-lactic acid in EtOAc.

The XRPD pattern and Raman spectrum of the L-lactate salt of Compound 1are provided in FIG. 16 and FIG. 17, respectively.

L-lactate salt form 1 had a crystalline XRPD pattern as shown in FIG.86.

A list of X-Ray Diffraction Peaks for L-lactate salt form 1 is providedbelow in Table 53.

TABLE 53 X-Ray Diffraction Peaks for L-lactate salt form 1 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 5.7715.31 8567.29 2702.27 7.93 11.14 3707.79 805.07 9.57 9.23 6536.451744.37 9.81 9.01 5422.84 1229.97 10.01 8.83 1286.33 278.79 11.69 7.57636.44 442.22 12.09 7.31 659.47 257.86 12.81 6.91 438.13 130.72 13.726.45 2239.74 429.16 14.39 6.15 387.11 62.28 14.66 6.04 646.85 76.1516.10 5.50 9044.71 1801.13 16.89 5.25 1892.98 391.34 17.19 5.15 4152.74900.30 17.70 5.01 3726.05 856.48 18.89 4.69 4918.54 956.25 19.20 4.622551.89 508.03 19.54 4.54 3811.47 1914.07 19.72 4.50 3625.59 480.8520.16 4.40 24622.32 4477.86 20.43 4.34 2054.14 585.82 20.96 4.23 1108.89182.73 21.55 4.12 2279.40 428.08 21.84 4.07 3342.05 708.16 23.12 3.84334.58 125.71 24.22 3.67 7143.74 1642.85 24.67 3.61 699.39 99.43 24.923.57 1595.28 535.99 25.21 3.53 979.84 134.85 26.19 3.40 900.19 141.7827.06 3.29 1508.32 552.00 28.55 3.12 1353.80 327.88 29.20 3.06 591.65138.22 30.43 2.93 2605.13 525.52 32.82 2.73 602.22 261.32 34.36 2.61665.89 425.00 36.29 2.47 520.56 416.78

L-lactate salt form 2 had a crystalline XRPD pattern as shown in FIG.87.

A list of X-Ray Diffraction Peaks for L-lactate salt form 2 is providedbelow in Table 54.

TABLE 54 X-Ray Diffraction Peaks for L-lactate salt form 2 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 9.699.12 14394.35 3150.69 10.23 8.64 19279.06 4326.72 12.14 7.28 4313.131293.87 12.74 6.94 2068.86 442.28 13.29 6.66 9625.97 2982.37 13.51 6.552764.22 395.72 15.62 5.67 1891.97 318.80 16.05 5.52 2662.84 703.09 16.295.44 6298.25 1046.32 16.87 5.25 6862.45 973.00 17.02 5.20 27914.565175.78 17.55 5.05 9048.65 2680.58 18.00 4.92 1471.27 529.76 18.51 4.7921485.38 3960.06 18.97 4.67 53356.51 10660.90 19.47 4.55 36315.488047.20 20.41 4.35 22065.68 4792.69 20.98 4.23 2383.55 855.63 21.45 4.145586.68 748.31 22.39 3.97 4949.80 489.75 22.64 3.93 4626.59 1873.2623.08 3.85 5876.13 934.80 23.50 3.78 936.23 177.40 23.84 3.73 14622.611862.43 24.03 3.70 11506.27 1924.85 24.46 3.64 2237.05 807.56 24.88 3.582294.50 303.94 25.21 3.53 1877.24 193.86 26.42 3.37 1045.35 469.22 26.863.32 4712.78 900.78 27.24 3.27 1985.74 467.48 27.77 3.21 5853.58 947.7228.23 3.16 5844.76 983.05 28.53 3.13 2717.46 528.27 30.47 2.93 3981.65827.52 31.04 2.88 1908.37 610.28 31.58 2.83 1072.02 246.27 32.44 2.761114.10 614.50 33.93 2.64 1246.80 704.44 35.53 2.52 1078.89 391.53 36.582.45 2105.60 666.00 37.11 2.42 2175.79 352.14 38.68 2.33 1282.85 404.00

In the TGA/DSC thermogram of the L-lactate salt form 2 (FIG. 39),continuous weight loss upon heating was noticed in TGA result startingfrom around 76.5° C. Total weight loss of 1.74% upon heating to 119.9°C. was attributed to the water content in the sample. An endothermicpeak with an onset temperature of 145.3° C. in DSC curve was associatedwith significant weight loss in the same temperature range of TGA curve,showing the decomposition of the salt, which was confirmed by additionalexperiments.

The sorption/desorption of the L-lactate salt form 2 is presented inFIG. 52, indicating the L-lactate salt is moderately hygroscopic. Asshown in FIG. 53, the XRPD pattern of the solid residues after DVS testis the same as that of the initial material.

As presented in FIG. 67, the XRPD patterns of Compound 1 L-lactate saltform 2 under stress conditions were different from that of the initialmaterial, implying that it was not physically stable under 80° C. and80° C./75% RH conditions for 2 weeks.

6.10.5.6. L-Malate Salt of Compound 1

L-malate salt form 1 was prepared by evaporation of a solutioncomprising Compound 1 and L-malic acid in ACN. L-malate salt form 2 wasprepared by evaporation of a solution comprising Compound 1 and L-malicacid in MeNO₂. L-malate salt form 3 was prepared by evaporation of asolution comprising Compound 1 and L-malic acid in EtOAc. L malate saltform 4 was prepared by evaporation of a solution comprising Compound 1and L malic acid in IPA. The ¹H NMR of the L-malate salt indicated thestoichiometry was approximately 1:1 for Compound 1 free base to L-malicacid.

The XRPD pattern and Raman spectrum of the L-malate salt of Compound 1are provided in FIG. 18 and FIG. 19, respectively.

L-malate salt form 1 had a crystalline XRPD pattern as shown in FIG. 90.

A list of X-Ray Diffraction Peaks for L-malate salt form 1 is providedbelow in Table 55.

TABLE 55 X-Ray Diffraction Peaks for L-malate salt form 1 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 5.5216.00 4650.06 1374.78 15.86 5.58 299.26 130.32 17.18 5.16 317.48 150.5011.12 N/A N/A N/A

L-malate salt form 2 had a crystalline XRPD pattern as shown in FIG. 91.

A list of X-Ray Diffraction Peaks for L-malate salt form 2 is providedbelow in Table 56.

TABLE 56 X-Ray Diffraction Peaks for L-malate salt form 2 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 5.4816.13 14241.11 3831.12 6.15 14.37 14244.61 3895.02 7.56 11.68 10677.312313.60 8.50 10.40 1379.75 235.51 8.99 9.83 1009.51 155.58 9.50 9.302937.00 553.28 11.08 7.98 1857.08 413.05 12.21 7.24 1578.33 648.91 12.976.82 7502.51 2057.41 15.23 5.81 9224.98 2018.74 16.09 5.50 3458.62904.54 17.16 5.16 7349.85 1813.80 17.50 5.06 5177.60 943.59 18.01 4.922362.53 418.22 18.48 4.80 8401.92 2975.75 19.21 4.62 774.16 76.11 19.694.51 3989.92 797.59 20.38 4.35 1302.47 133.59 21.09 4.21 19457.714307.14 21.75 4.08 1674.61 558.12 22.47 3.95 3942.16 786.38 22.72 3.912402.73 634.11 23.70 3.75 878.23 191.72 24.44 3.64 5993.43 1304.05 24.963.56 2237.93 303.32 25.23 3.53 1430.80 183.14 25.80 3.45 1115.60 224.9326.20 3.40 1083.00 130.42 26.51 3.36 602.65 101.81 27.78 3.21 1833.76663.95 28.41 3.14 828.83 162.67 30.01 2.98 588.93 107.33 30.41 2.945575.15 1101.91 32.95 2.72 713.94 167.61 34.90 2.57 1206.98 144.36 35.282.54 381.13 132.40 35.91 2.50 1060.42 208.28 36.41 2.47 506.65 110.7137.63 2.39 666.57 168.88

L-malate salt form 3 had a crystalline XRPD pattern as shown in FIG. 92.

A list of X-Ray Diffraction Peaks for L-malate salt form 3 is providedbelow in Table 57.

TABLE 57 X-Ray Diffraction Peaks for L-malate salt form 3 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 4.8918.05 733.52 196.88 5.49 16.08 476.34 148.29 7.25 12.19 388.59 110.6011.74 7.53 161.95 23.13 12.39 7.14 77.69 25.95 15.76 5.62 302.26 59.6416.34 5.42 92.28 11.80 16.73 5.29 82.14 17.20 19.79 4.48 93.50 14.9820.54 4.32 139.31 31.59 21.23 4.18 36.88 13.01

L-malate salt form 4 had a crystalline XRPD pattern as shown in FIG. 93.

A list of X-Ray Diffraction Peaks for L-malate salt form 4 is providedbelow in Table 58.

TABLE 58 X-Ray Diffraction Peaks for L-malate salt form 4 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 5.9114.94 31637.83 7073.58 8.34 10.59 450.62 50.16 10.45 8.46 446.51 49.2810.91 8.10 7690.41 1510.86 12.67 6.98 1733.49 464.77 13.10 6.75 632.99112.97 13.48 6.56 1569.65 343.67 15.34 5.77 915.97 115.48 16.71 5.301049.18 138.54 17.49 5.07 1003.54 201.55 17.89 4.95 1244.11 301.16 18.224.86 3801.22 515.07 18.72 4.74 8609.34 1276.65 18.95 4.68 1225.87 395.2019.41 4.57 584.23 104.52 19.84 4.47 888.59 99.41 20.21 4.39 778.79107.30 20.77 4.27 7772.45 1151.69 21.22 4.18 6019.34 958.38 21.62 4.111469.36 225.07 21.91 4.05 3933.61 810.69 22.60 3.93 1554.17 343.06 23.993.71 1702.59 388.26 24.56 3.62 1954.61 312.65 25.03 3.55 1382.95 222.5726.20 3.40 3053.38 513.08 27.19 3.28 378.84 50.65 27.52 3.24 1327.44297.07 28.45 3.13 1262.11 258.60 29.19 3.06 1040.34 204.72 29.60 3.02375.40 39.46 29.96 2.98 263.41 37.89 30.24 2.95 514.98 44.48 30.99 2.88644.29 151.37 31.61 2.83 1501.73 260.48 34.44 2.60 891.98 204.00 35.662.52 268.17 104.49 36.10 2.49 187.33 47.19 36.86 2.44 390.94 58.41 37.192.42 190.16 78.86 37.83 2.38 689.68 97.30 38.58 2.33 469.32 68.49 39.052.30 250.12 29.00

In the TGA/DSC thermogram of the L-malate salt form 2 (FIG. 38), 1.21%weight loss upon heating to 94.8° C. on TGA is attributed to the watercontent in the material. Multiple endothermic events were observed inDSC results. The first one with an onset temperature of 100.8° C. waslikely a solid-solid transition. The second one was followed by a broadthird one, corresponding to the temperature range with continuous andsignificant weight loss on TGA, implying melting and decompositionoccurred.

The sorption/desorption of L-malate salt form 2 is presented in FIG. 50,indicating the L-malate salt is a hygroscopic material. As shown in FIG.51, the XRPD pattern of the solid residues after DVS test is differentfrom that of the initial material.

As presented in FIG. 66, the XRPD patterns of Compound 1 L-malate saltunder stress conditions were different from that of the initialmaterial, showing that it was not physically stable under 80° C. and 80°C./75% RH conditions for 2 weeks.

6.10.5.7. Citrate Salt of Compound 1

The citrate salt of Compound 1 was prepared by evaporation of a solutioncomprising Compound 1 and citric acid in MTBE, MeNO₂, Hexane or MeOAc.The XRPD patterns in FIG. 20 and Raman spectra in FIG. 21 of the citratesalt showed that the citrate salt was amorphous. The ¹H NMR of thecitrate salt indicated that the stoichiometry was approximately 1:1 forCompound 1 free base to citric acid.

6.10.5.8. Succinate Salt of Compound 1

Succinate salt form 1 was prepared by evaporation of a solutioncomprising Compound 1 and succinic acid in ACN or EtOH. Succinate saltform 2 was prepared by evaporation of a solution comprising Compound 1and succinic acid in EtOAc. When acetone was used to crystallize thesuccinate salt, a mix of succinate salt (form 1) and free base (form B)was obtained.

The XRPD patterns and Raman spectra of succinate salt forms 1-2 areprovided in FIG. 22 and FIG. 23, respectively.

Succinate salt form 1 had a crystalline XRPD pattern as shown in FIG.94.

A list of X-Ray Diffraction Peaks for succinate salt form 1 is providedbelow in Table 59.

TABLE 59 X-Ray Diffraction Peaks for succinate salt form 1 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 5.8615.06 741560.16 134011.71 8.43 10.48 3428.24 566.75 11.07 7.98 8866.341152.28 11.79 7.50 19251.74 3571.33 12.67 6.98 1055.18 744.64 13.55 6.532868.66 662.80 13.69 6.46 5459.82 1133.49 14.47 6.12 481.50 186.09 16.845.26 4915.24 643.73 17.38 5.10 598.40 112.44 17.74 4.99 8286.93 1474.5418.77 4.72 10169.14 1725.47 18.97 4.67 1406.15 163.65 19.22 4.61 3386.12762.14 20.59 4.31 729.25 113.97 21.11 4.21 2468.42 599.98 21.33 4.167483.04 1362.99 21.43 4.14 4898.23 317.40 21.83 4.07 4564.87 614.7321.90 4.06 12063.81 1567.35 22.23 4.00 1810.53 450.35 22.78 3.90 1062.85212.49 23.74 3.75 37058.08 6170.46 23.97 3.71 4975.30 962.00 24.84 3.582097.14 474.48 25.12 3.54 4306.68 1112.62 26.29 3.39 12976.02 2215.8427.42 3.25 901.22 159.21 28.10 3.17 1659.85 238.74 28.20 3.16 2429.80274.68 28.39 3.14 2613.39 471.94 28.88 3.09 530.93 114.42 29.35 3.042131.21 381.64 29.57 3.02 4295.83 753.04 29.82 2.99 1459.99 215.81 30.882.89 390.60 55.20 31.61 2.83 10632.06 1942.82 33.87 2.64 768.10 98.2234.33 2.61 2622.97 624.69 35.36 2.54 649.18 395.76 39.11 2.30 155.0561.13 39.85 2.26 1061.88 215.57

Succinate salt form 2 had a crystalline XRPD pattern as shown in FIG.95.

A list of X-Ray Diffraction Peaks for succinate salt form 2 is providedbelow in Table 60.

TABLE 60 X-Ray Diffraction Peaks for succinate salt form 2 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 5.6915.53 3116.38 1013.59 5.90 14.96 2015.61 643.95 6.18 14.28 715.27 222.8511.02 8.02 207.22 62.21 16.48 5.38 55.16 39.67 17.31 5.12 68.01 20.0318.49 4.80 176.59 105.39 20.99 4.23 221.29 157.64 22.30 3.98 72.49 20.8323.16 3.84 52.32 12.42 29.01 3.08 69.12 23.39 30.85 2.90 53.51 26.22

6.10.5.9. Tosylate Salt of Compound 1

Tosylate salt form 1 was prepared by evaporation of a solutioncomprising Compound 1 and p-toluenesulfonic acid in ACN. Tosylate saltform 2 was prepared by evaporation of a solution comprising Compound 1and p-toluenesulfonic acid in MeNO₂ or acetone. Tosylate salt form 3 wasprepared by evaporation of a solution comprising Compound 1 andp-toluenesulfonic acid in EtOAc.

The XRPD patterns and Raman spectra of tosylate salt forms 1-3 areprovided in FIG. 24 and FIG. 25, respectively.

Tosylate salt form 1 had a crystalline XRPD pattern as shown in FIG. 96.

A list of X-Ray Diffraction Peaks for tosylate salt form 1 is providedbelow in Table 61.

TABLE 61 X-Ray Diffraction Peaks for tosylate salt form 1 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 4.5019.63 1119.48 481.74 6.22 14.19 24089.25 8683.84 8.88 9.95 7912.382783.78 9.55 9.26 2286.05 1003.10 9.67 9.14 1996.14 635.37 12.19 7.255448.92 1717.40 13.25 6.68 3136.11 1011.98 13.89 6.37 7529.57 3315.1214.86 5.96 1281.58 310.08 15.71 5.64 3137.73 1037.40 17.14 5.17 5481.821566.01 17.73 5.00 3531.02 981.24 18.29 4.85 1046.09 317.43 18.63 4.763683.67 904.17 19.45 4.56 3896.87 2042.03 19.90 4.46 3285.04 1187.1121.06 4.22 2293.12 665.02 21.71 4.09 10614.44 4550.98 22.64 3.92 3981.341553.01 23.12 3.84 2237.02 752.41 23.88 3.72 875.58 528.34 24.27 3.661288.84 419.54 25.43 3.50 2133.47 487.47 25.84 3.45 2652.92 1354.5726.06 3.42 780.65 259.53 26.37 3.38 1293.11 194.96 27.71 3.22 1001.90400.92 28.45 3.13 241.26 52.80 28.82 3.10 650.54 207.73 29.20 3.06983.94 309.44 30.62 2.92 745.67 355.19 31.45 2.84 837.77 432.24 33.812.65 163.76 156.52 34.89 2.57 833.87 343.43 35.38 2.54 547.37 179.19

Tosylate salt form 2 had a crystalline XRPD pattern as shown in FIG. 97.

A list of X-Ray Diffraction Peaks for tosylate salt form 2 is providedbelow in Table 62.

TABLE 62 X-Ray Diffraction Peaks for tosylate salt form 2 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 5.7815.28 3129.35 882.17 6.24 14.15 6413.58 1705.19 6.48 13.64 6310.571602.31 7.01 12.60 1270.40 460.48 8.13 10.87 12819.37 3032.70 9.79 9.021209.06 355.63 11.67 7.57 12054.78 2902.12 12.04 7.35 749.22 232.5912.60 7.02 4656.33 1144.98 14.25 6.21 5771.80 1204.84 15.04 5.88 8508.731766.00 15.57 5.69 1201.06 370.24 16.42 5.39 4471.53 1074.22 17.53 5.051492.46 287.52 18.13 4.89 976.97 133.25 18.31 4.84 4582.65 1701.91 18.894.69 5274.72 1700.42 19.55 4.54 1069.93 261.06 19.90 4.46 1094.61 247.1021.36 4.16 4435.48 761.82 21.61 4.11 3758.93 882.67 21.94 4.05 853.7388.40 22.49 3.95 3570.30 888.13 22.74 3.91 1446.33 273.00 23.05 3.851650.81 342.85 23.35 3.81 3441.60 887.49 23.59 3.77 7432.65 1530.8824.36 3.65 2344.93 768.09 24.55 3.62 1568.96 315.09 25.53 3.49 1864.52430.70 25.78 3.45 1116.10 249.08 26.54 3.36 2153.07 378.46 27.40 3.251360.83 449.11 28.07 3.18 408.48 52.86 28.49 3.13 415.91 113.26 29.323.04 386.23 223.04 30.44 2.93 478.73 207.01 32.58 2.75 266.35 98.7733.16 2.70 222.84 50.13 33.62 2.66 556.86 70.67 35.52 2.53 601.40 341.0736.88 2.44 534.83 121.80

Tosylate salt form 3 had a crystalline XRPD pattern as shown in FIG. 98.

A list of X-Ray Diffraction Peaks for tosylate salt form 3 is providedbelow in Table 63.

TABLE 63 X-Ray Diffraction Peaks for tosylate salt form 3 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 5.5915.79 587.67 198.25 7.44 11.88 122.67 29.86 8.91 9.92 100.60 21.68 11.227.88 908.65 230.37 13.13 6.74 292.80 68.40 13.78 6.42 103.28 18.68 14.056.30 72.35 12.99 14.89 5.95 79.41 16.05 15.62 5.67 121.73 36.04 17.784.98 171.13 57.59 18.15 4.88 374.03 77.57 19.24 4.61 99.69 17.63 19.704.50 63.03 11.84 20.77 4.27 326.32 112.46 21.72 4.09 94.50 25.96 21.964.04 194.16 45.94 22.40 3.97 445.42 103.56 23.49 3.78 147.54 26.77 24.973.56 24.38 28.69 25.97 3.43 126.49 21.65 26.66 3.34 74.56 26.28 28.923.08 51.12 17.05 31.46 2.84 36.16 13.37

6.10.5.10. Mesylate Salt of Compound 1

Mesylate salt form 1 was prepared by evaporation of a solutioncomprising Compound 1 and methanesulfonic acid in ACN/IPA, EtOH/IPA oracetone. Mesylate salt form 2 was prepared by evaporation of a solutioncomprising Compound 1 and methanesulfonic acid in EtOAc.

The XRPD patterns and Raman spectra of mesylate salt forms 1-2 areprovided in FIG. 26 and FIG. 27, respectively.

Mesylate salt form 1 had a crystalline XRPD pattern as shown in FIG. 99.A list of X-Ray Diffraction Peaks for mesylate salt form 1 is providedbelow in Table 64.

TABLE 64 X-Ray Diffraction Peaks for mesylate salt form 1 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 5.7815.27 49300.59 12429.36 7.87 11.22 2955.99 658.99 10.30 8.58 2325.51514.54 10.71 8.25 5639.75 1233.98 11.61 7.62 4822.73 1387.64 11.86 7.462031.41 388.49 12.39 7.14 280.99 157.12 13.50 6.55 445.26 64.79 13.836.40 598.23 211.63 14.17 6.24 465.14 78.92 15.05 5.88 1537.55 238.8315.56 5.69 825.59 180.11 15.80 5.60 786.43 131.94 16.29 5.44 1183.68265.49 17.06 5.19 785.26 127.66 17.49 5.07 5376.19 1043.67 17.74 5.003356.48 525.78 18.10 4.90 6521.33 3902.46 18.30 4.84 8803.15 1056.3518.54 4.78 4331.78 791.47 19.25 4.61 2827.22 485.65 19.89 4.46 827.43147.02 20.18 4.40 2395.10 581.27 20.58 4.31 1565.50 448.98 20.98 4.231329.32 121.57 21.56 4.12 1098.02 435.12 21.95 4.05 1906.89 639.52 23.413.80 5886.15 1445.90 24.22 3.67 1175.84 298.88 24.82 3.58 1168.28 343.5425.53 3.49 999.98 330.62 26.08 3.41 1605.90 277.36 26.77 3.33 543.6269.86 27.27 3.27 620.56 264.06 28.17 3.16 1296.21 233.73 28.38 3.14713.11 401.95 29.03 3.07 659.20 119.89 29.31 3.04 983.25 231.03 29.872.99 568.74 211.56 30.81 2.90 272.77 78.25 32.02 2.79 557.29 117.3732.99 2.71 273.87 49.72 34.03 2.63 287.44 60.05 35.01 2.56 561.92 118.8335.45 2.53 369.17 165.89 35.72 2.51 436.77 75.30 36.33 2.47 223.38 39.7837.65 2.39 433.85 164.84

Mesylate salt form 2 had a crystalline XRPD pattern as shown in FIG.100.

A list of X-Ray Diffraction Peaks for mesylate salt form 2 is providedbelow in Table 65.

TABLE 65 X-Ray Diffraction Peaks for mesylate salt form 2 IntegratedIntensity Two-theta angle (°) d Space (Å) Height (cps) (cps deg) 5.1417.18 1551.90 358.84 5.26 16.79 2300.19 281.94 10.45 8.46 736.68 139.3716.37 5.41 85.61 14.32 18.36 4.83 379.10 102.32 20.41 4.35 215.89 34.8520.95 4.24 741.91 110.48 21.59 4.11 428.99 62.04 21.86 4.06 169.85 23.5922.14 4.01 60.71 4.84 22.63 3.93 75.07 9.44 23.33 3.81 152.57 17.2524.24 3.67 77.04 21.74 25.76 3.46 62.57 6.96 26.16 3.40 162.16 28.5328.41 3.14 88.28 19.20 31.70 2.82 102.91 24.75

6.10.5.11. Besylate Salt and Fumarate Salt of Compound 1

Only one sample was prepared for each acid, respectively. Both saltswere crystalline. The fumarate salt of Compound 1 was prepared byevaporation of a solution comprising Compound 1 and fumaric acid in ACN.The besylate salt of Compound 1 was prepared by evaporation of asolution comprising Compound 1 and benzenesulfonic acid in MeNO₂. The ¹HNMR spectrum of the fumarate salt indicated that the fumarate salt waslikely a hemi-fumarate, i.e., stoichiometry of free base to fumaric acidwas 2:1.

The XRPD patterns and Raman spectra of besylate salt and fumarate saltof compound 1 were presented in FIG. 28 and FIG. 29, respectively.

Besylate salt had a crystalline XRPD pattern as shown in FIG. 101.

A list of X-Ray Diffraction Peaks for besylate salt is provided below inTable 66.

TABLE 66 X-Ray Diffraction Peaks for besylate salt Integrated IntensityTwo-theta angle (°) d Space (Å) Height (cps) (cps deg) 6.29 14.0410079.20 3370.84 7.84 11.27 792.75 108.46 9.64 9.17 1715.74 623.01 11.327.81 3068.41 767.79 12.63 7.00 714.46 137.04 14.38 6.15 4085.73 987.1115.89 5.57 598.93 455.05 16.81 5.27 2062.26 484.07 17.44 5.08 985.62403.57 19.09 4.64 1730.10 327.29 19.39 4.57 2021.88 847.60 19.82 4.48413.42 87.69 20.31 4.37 753.15 141.36 20.79 4.27 2156.74 598.02 21.634.10 624.78 148.57 22.35 3.97 913.49 366.36 22.82 3.89 1781.71 366.7423.87 3.72 1699.23 656.68 25.30 3.52 1057.85 298.77 26.12 3.41 637.04289.25 27.64 3.22 1214.57 597.64 28.94 3.08 613.67 331.12 34.90 2.57274.40 63.34

Fumarate salt had a crystalline XRPD pattern as shown in FIG. 102.

A list of X-Ray Diffraction Peaks for fumarate salt is provided below inTable 67.

TABLE 67 X-Ray Diffraction Peaks for fumarate salt Integrated IntensityTwo-theta angle (°) d Space (Å) Height (cps) (cps deg) 5.97 14.80252492.33 70173.05 8.31 10.64 2370.62 521.48 11.09 7.97 6488.86 2230.8011.92 7.42 633.10 177.24 12.38 7.15 1824.49 447.50 12.97 6.82 3300.75845.78 13.53 6.54 2169.17 551.07 14.72 6.01 749.76 283.35 15.81 5.601083.00 318.56 16.66 5.32 1114.36 220.75 18.51 4.79 1692.29 391.66 18.924.69 5992.99 1732.71 20.94 4.24 2922.64 569.38 21.36 4.16 13242.362930.78 21.76 4.08 4393.51 1792.16 22.34 3.98 1433.13 337.27 23.33 3.81578.80 247.32 24.08 3.69 3172.91 1022.18 24.65 3.61 2885.09 647.85 25.583.48 599.14 238.98 26.31 3.38 11075.59 2579.03 28.74 3.10 2691.701069.09 29.20 3.06 2323.12 711.80 29.83 2.99 1118.39 279.20 30.96 2.89118.24 128.75 31.72 2.82 6110.27 1748.30 34.86 2.57 774.22 423.28 36.342.47 414.89 293.99

6.10.6. Salt Scale-Up Results

The crystalline salt forms observed from the screening study, i.e., HCl(form 2), H₂SO₄ (form 1), H₃PO₄ (form 1), L-tartrate (form 1,hemi-tartrate hydrate), L-malate (form 2) and L-lactate (form 2), weresuccessfully scaled up and characterized along with the free base.

The concentrations of acids were different from those used in the saltscreening experiments. The amounts of Compound 1 and acids used for saltscale-up were summarized in Table 68.

TABLE 68 Compound 1 Salt Scale-up Molar MeOH/ Acid Acid ratio of Cmpd 1Cmpd 1 DCM conc. used Cmpd Sample (mg) (mmole) (mL) (mol/L) (μL) 1/AcidHCl 361.4 1.124 20.0 12.0 94.0 1 H₂SO₄ 311.9 0.970 20.0 18.4 53.0 1H₃PO₄ 299.5 0.932 20.0 15.2 62.0 1 L-lactate 357.7 1.113 20.0 0.6491715.0 1 L-tartrate 262.5 0.817 20.0 0.525 779.0 2 L-malate 277.0 0.86220.0 0.479 1801.0 1

The free base of Compound 1 was weighed and dissolved in MeOH/DCM, thenmixed with the acidic counter-ion solution based on the specified molarratio in a 40 mL clear glass vial. The vial was then capped and shakenat 200 RPM at ambient temperature for 2 hours. Afterwards, the cap wasremoved and the vial was stored in fume hood for drying under nitrogenpurge. Re-crystallization solvent was then added to the sample togenerate a suspension sample. All salts were prepared in the sameprocedure. The final 6 mL of re-crystallization solvents were added intothe samples as follows:

IPA to the HCl salt sample;

IPA to the H₂SO₄ salt sample;

EtOAc to the H₃PO₄ salt sample;

Acetone to the L-tartrate salt sample;

Nitromethane and acetone of 1 mL to the L-malate salt sample; and

n-Hexane to the L-lactate salt sample.

In addition, both L-malate sample and L-lactate sample were seeded withcrystalline sample obtained during salt screening using thecorresponding counter-ion, respectively.

All samples in the re-crystallization solvents were stirred withstirring bars at ambient temperature for approximately 3 days. They werefiltered using 0.2 m Nylon-membraned centrifuge tube filters at 14000RPM for 5 min, respectively. The solids were covered and dried in vacuumoven at ambient temperature for 2 days. Both the HCl salt and L malatesalt were further dried in vacuum oven at 60° C. for one day after ¹HNMR tests indicated they contained small amount of re-crystallizationsolvents. The H₂SO₄ salt was re-slurried in n-Hexane and recoveredthrough filtration and drying in vacuum oven at 60° C. overnight.

At the end, both salts and free base were stored in closed vials atambient temperature prior to analyses using a variety of solid statecharacterization techniques. The compounds used were free base (form A),HCl salt (form 2), H₂SO₄ salt (form 1), H₃PO₄ salt (form 1), L-tartratesalt (form 1), L-malate salt (form 2) and L-lactate salt (form 2).

6.10.7. Solid State Stability

Physical Stability:

A portion of the sample was loaded to a 4 mL clear glass vial. Foursamples were prepared for each salt. The vials (open) were stored under4 different stress conditions, respectively. The stress conditions were40° C., 40° C./75% RH, 80° C. and 80° C./75% RH. Temperature wascontrolled using ovens and 75% RH was controlled using saturated sodiumchloride solution in water. At the two-week time point, the samplesstored at 80° C. and 80° C./75% RH were removed for analysis using XRPD.

Chemical Stability:

Approximately 1 mg of Compound 1 was accurately weighed to a 4 mL clearglass vial. Six vials were prepared for each salt. Two samples werestored in the refrigerator. The other four samples in open vials werestored under 4 stress conditions, respectively. At the two-week timepoint, the samples stored at 80° C. and 80° C./75% RH were removed,dissolved in solvent and assayed using HPLC with UV detection afterappropriate dilution. One set of samples stored in the refrigerator wereused to prepare the stock and standard solutions. The HPLC method waspresented in Table 69.

TABLE 69 HPLC Method HPLC System alliance e2695 Separation Module with2998 Photodiode Array Detector Software Empower2 Mobile Phase A 0.1%(v/v) formic acid in water Mobile Phase B 0.1% (v/v) formic acid in MeOHColumn Phenomenex Gemini-NX, 5 μ C18, 110 Å, 250 × 4.6 mm, Cat#00G-4454-E0, SN# 614022-11 Column Ambient Temperature Flow Rate 1.0mL/min Injection Volume 10 μL Detection PDA range of 210-400 nm and UVat 254 nm Run Time 25 minutes Gradient profile Time (minute) % A % B 0.085 15 0.25 85 15 20.0 0 100 23.0 0 100 24.0 85 15 25.0 85 15

As presented in Table 70, the remaining percentages for free base andsalts were within %100±2 except for the L-malate salt, showing the freebase and salts were chemically stable under 80° C. and 80° C./75% RHconditions for 2 weeks except for the L-malate salt. The chromatogramsare presented in FIG. 68, FIG. 69, FIG. 70, FIG. 71, FIG. 72, FIG. 73and FIG. 74, respectively. Although extra peaks were observed for thesalt except for the free base and L-malate salt, the peak areapercentage was <0.1%. As to the L-malate salt, significant degradationsoccurred, therefore it was not chemically stable under stressconditions.

TABLE 70 Remaining Percentage of Compound 1 Free Base and Salts underStress Conditions Com- Free L-tar- L-ma- L-lac- pound base HCl H₂SO₄H₃PO₄ trate late tate % Remain- 101.8 101.2 100.0 101.1 98.7 87.7 100.4ing at 80° C. % Remain- 100.8 100.4 100.1 99.9 98.3 92.9 100.5 ing at80° C./ 75% RH

6.10.8. Conclusions

Crystalline salts were obtained from 11 of 13 acidic counter-ions usedin this study. All salts exhibited higher solubility than the free basein water. Except for the L-malate salt, all salts and free base werechemically stable under 80° C. and 80° C./75% RH for 2 weeks. Compound 1(free base), the H₃PO₄ salt and L-tartrate salt were physically stableunder stress conditions. The HCl salt and H₂SO₄ salt were stable under80° C. condition but not under 80° C./75% RH. The L-lactate salt was notphysically stable under stress conditions. The L-malate salt was neitherphysically nor chemically stable under stress condition. Compound 1(free base), the H₃PO₄ salt and L-tartrate salt (hydrate) were nothygroscopic. The L-lactate salt was moderately hygroscopic and othersalts were hygroscopic.

A number of references have been cited, the disclosures of which areincorporated herein by reference in their entirety.

What is claimed is:
 1. A method for treating a disease or disordertreatable by inhibition of a JNK pathway, comprising administering to apatient having the disease or disorder an effective amount of apharmaceutical composition comprising about 20-40% by weight of2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamideor a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate,isotopologue or solid form thereof, about 30-50% by weight ofmicrocrystalline cellulose, about 20-40% by weight of mannitol, about1-10% by weight of carboxymethyl cellulose, about 1-10% by weight ofhydroxypropyl methylcellulose and about 0.1-2% by weight of magnesiumstearate, wherein the disease or disorder is a liver fibrotic disorder,diabetes or a metabolic syndrome leading to liver fibrotic disorders. 2.The method of claim 1, wherein the disease or disorder is a liverfibrotic disorder.
 3. The method of claim 1, wherein the disease ordisorder is diabetes.
 4. The method of claim 1, wherein the disease ordisorder is a metabolic syndrome leading to liver fibrotic disorders. 5.A method for treating a disease or disorder, comprising administering toa patient having the disease or disorder an effective amount of apharmaceutical composition comprising about 20-40% by weight of2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamideor a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate,isotopologue or solid form thereof, about 30-50% by weight ofmicrocrystalline cellulose, about 20-40% by weight of mannitol, about1-10% by weight of carboxymethyl cellulose, about 1-10% by weight ofhydroxypropyl methylcellulose and about 0.1-2% by weight of magnesiumstearate, wherein the disease or disorder is interstitial pulmonaryfibrosis, systemic sclerosis, scleroderma, chronic allograftnephropathy, antibody mediated rejection or lupus.
 6. The method ofclaim 4, wherein the disease or disorder is interstitial pulmonaryfibrosis.
 7. A salt of2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide,wherein the salt is a hydrochloride salt, a sulfate salt, a phosphatesalt, an L-tartrate salt, an L-malate salt, an L-lactate salt, asuccinate salt, a p-toluenesulfate salt, a methanesulfate salt, abenzensulfate salt, a fumarate salt or a citrate salt.
 8. A method fortreating a disease or disorder treatable by inhibition of a JNK pathway,comprising administering to a patient having the disease or disorder aneffective amount of the salt of claim
 7. 9. A method for treatinginterstitial pulmonary fibrosis, systemic sclerosis, scleroderma,chronic allograft nephropathy, antibody mediated rejection or lupus,comprising administering to a patient having interstitial pulmonaryfibrosis, systemic sclerosis, scleroderma, chronic allograftnephropathy, antibody mediated rejection or lupus an effective amount ofthe salt of claim
 7. 10. The method of claim 7, wherein the disease ordisorder is interstitial pulmonary fibrosis.
 11. The method of claim 1,wherein the pharmaceutical composition comprises about 28.57% by weightof2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamideor a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate,isotopologue or solid form thereof, about 37.43% by weight ofmicrocrystalline cellulose, about 26% by weight of mannitol, about 4% byweight of carboxymethyl cellulose, about 3% by weight of hydroxypropylmethylcellulose and about 1% by weight of magnesium stearate.
 12. Themethod of claim 1, wherein pharmaceutical composition comprises about28.57% by weight of2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamideor a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate,isotopologue or solid form thereof, about 33.43% by weight ofmicrocrystalline cellulose, about 26% by weight of mannitol, about 8% byweight of carboxymethyl cellulose, about 3% by weight of hydroxypropylmethylcellulose and about 1% by weight of magnesium stearate.
 13. Themethod of claim 1, wherein pharmaceutical composition comprises about28.57% by weight of2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamideor a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate,isotopologue or solid form thereof, about 31.93% by weight ofmicrocrystalline cellulose, about 26% by weight of mannitol, about 8% byweight of carboxymethyl cellulose, about 4.5% by weight of hydroxypropylmethylcellulose and about 1% by weight of magnesium stearate.
 14. Themethod of claim 1, wherein pharmaceutical composition comprises about28.57% by weight of2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamideor a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate,isotopologue or solid form thereof, about 35.93% by weight ofmicrocrystalline cellulose, about 26% by weight of mannitol, about 4% byweight of carboxymethyl cellulose, about 4.5% by weight of hydroxypropylmethylcellulose and about 1% by weight of magnesium stearate.
 15. Themethod of claim 5, wherein the pharmaceutical composition comprisesabout 28.57% by weight of2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamideor a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate,isotopologue or solid form thereof, about 37.43% by weight ofmicrocrystalline cellulose, about 26% by weight of mannitol, about 4% byweight of carboxymethyl cellulose, about 3% by weight of hydroxypropylmethylcellulose and about 1% by weight of magnesium stearate.
 16. Themethod of claim 5, wherein pharmaceutical composition comprises about28.57% by weight of2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamideor a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate,isotopologue or solid form thereof, about 33.43% by weight ofmicrocrystalline cellulose, about 26% by weight of mannitol, about 8% byweight of carboxymethyl cellulose, about 3% by weight of hydroxypropylmethylcellulose and about 1% by weight of magnesium stearate.
 17. Themethod of claim 5, wherein pharmaceutical composition comprises about28.57% by weight of2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamideor a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate,isotopologue or solid form thereof, about 31.93% by weight ofmicrocrystalline cellulose, about 26% by weight of mannitol, about 8% byweight of carboxymethyl cellulose, about 4.5% by weight of hydroxypropylmethylcellulose and about 1% by weight of magnesium stearate.
 18. Themethod of claim 5, wherein pharmaceutical composition comprises about28.57% by weight of2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamideor a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate,isotopologue or solid form thereof, about 35.93% by weight ofmicrocrystalline cellulose, about 26% by weight of mannitol, about 4% byweight of carboxymethyl cellulose, about 4.5% by weight of hydroxypropylmethylcellulose and about 1% by weight of magnesium stearate.